CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial No. 63/129,229, filed on December 22, 2020, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present disclosure relates to, in part, methods of treating a subject, e.g., a subject having cancer, which include administration of a STING antagonist or a cGAS inhibitor.

BACKGROUND

The cGAS/STING (cyclic GMP-AMP Synthase/Stimulator of Interferon Genes) pathway is a component of inflammatory signaling pathways. When DNA is present in the cytosol of a cell, cGAS binds it and generates 2’ -5’ cyclic GMP-AMP (cGAMP). Activated by cGAMP, STING induces the phosphorylation of and nuclear translocation of interferon (IFN) regulatory factors (IRFs). As transcription factors, IRFs regulate the expression of genes, including the type I IFNs, which regulate the activity of the immune system.

The presence of DNA in the cytosol of a cell can sometimes be the result of an infection. In some cases, the presence of DNA in the cytosol of a cell can be the result of DNA damage in the nucleus of a cell or in the mitochondria of a cell. In some instances, the cytosolic DNA is degraded or modified by enzymes to prevent activation of the cGAS/STING pathway. SUMMARY

The present disclosure is based on the discovery that cancer cells having decreased ATM level and/or activity are more sensitive to treatment with a STING antagonist or a cGAS inhibitior, e.g., than cells that do not have decreased ATM level and/or activity.

Provided herein are methods of treating a subject in need thereof that include: (a) identifying a subject having a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level; and (b) administering a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.

Also provided herein are methods of treating a subject in need thereof that include administering a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level.

Also provided herein are methods of selecting a treatment for a subject in need thereof that include: (a) identifying a subject having a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of selecting a treatment for a subject in need thereof that include selecting a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level.

Also provided herein are methods of selecting a subject for treatment that include: (a) identifying a subject having a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level; and (b) selecting the identified subject for treatment with a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of selecting a subject for participation in a clinical trial that include: (a) identifying a subject having a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level; and (b) selecting the identified subject for participation in a clinical trial that comprises administration of a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of selecting a subject for participation in a clinical trial that include selecting a subject identified as having a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level, for participation in a clinical trial that comprises administration of a treatment comprising a therapeutically effective amount of a STING antagonist or a cGAS inhibitor, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of predicting a subject’s responsiveness to a STING antagonist or cGAS inhibitor that include: (a) determining that a subject has a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level; and (b) identifying that the subject determined to have decreased ATM expression and/or activity in a tumor sample obtained from the subject as compared to a reference level, in step (a) has an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor.

Also provided herein are methods of predicting a subject’s responsiveness to a STING antagonist or cGAS inhibitor that include identifying a subject determined to have a cancer cell having decreased ATM level and/or activity in a tumor sample obtained from the subject as compared to a reference level, as having an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor. In some embodiments of any of the methods described herein, the subject is identified having a cancer cell having both (i) decreased ATM level and/or activity and (ii) increased cGAS/STING signaling pathway activity, as compared to a reference level; and optionally wherein the subject is identified as having an elevated level of cGAMP in a serum or tumor sample obtained from the subject as compared to a reference level.

In some embodiments of any of the methods described herein, the decreased ATM level and/or activity is a result of loss of one or both alleles of an ATM gene in the subject. In some embodiments of any of the methods described herein, the decreased ATM level and/or activity is a result of a mutation in one or both alleles of an ATM gene in the subject.

In some embodiments of any of the methods described herein, the method further includes administering the selected treatment to the subject. In some embodiments of any of the methods described herein, the method further includes administering a therapeutically effective amount of a STING antagonist or a cGAS inhibitor to a subject identified as having an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor.

In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having a cancer, such as a cancer selected from the group consisting of: renal clear cell carcinoma, kidney renal papillary cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having a cancer, such as a cancer selected from the group consisting of: renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

In some embodiments of any of the methods described herein, the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of any of the methods described herein, the STING antagonist or the cGAS inhibitor is a compound selected from the group consisting of the compounds in Tables C1-C2, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. As used herein, the term “STING antagonist” is an agent that decreases one or both of (i) the activity of STING (e.g., any of the exemplary activities of STING described herein) (e.g., as compared to the level of STING activity in the absence of the agent) and (ii) the expression level of STING in a mammalian cell (e.g., using any of the exemplary methods of detection described herein) (e.g., as compared to the expression level of STING in a mammalian cell not contacted with the agent). Non-limiting examples of STING antagonists are described herein.

As used herein, the term “STING” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

As used herein, the term “ATM” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

As used herein, the term “cGAS inhibitor” is an agent that decreases one or both of (i) the activity of cGAS (e.g., any of the exemplary activities of cGAS described herein) (e.g., as compared to the level of cGAS activity in the absence of the agent) and (ii) the expression level of cGAS in a mammalian cell (e.g., using any of the exemplary methods of detection described herein) (e.g., as compared to the expression level of cGAS in a mammalian cell not contacted with the agent). Non-limiting examples of cGAS inhibitors are described herein.

As used herein, the term “cGAS” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous cGAS molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof. The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a STING antagonist or cGAS inhibitor being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a STING antagonist or cGAS inhibitor disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

The term “pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term “pharmaceutically acceptable salt” may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acidic group with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salts not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein from with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine, and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a STING antagonist or cGAS inhibitor with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the STING antagonist or cGAS inhibitor to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human. In some embodiments of any of the methods described herein, the subject is 1 year old or older, 2 years old or older, 4 years old or older, 5 years old or older, 10 years old or older, 12 years old or older, 13 years old or older, 15 years old or older, 16 years old or older, 18 years old or older, 20 years old or older, 25 years old or older, 30 years old or older, 35 years old or older, 40 years old or older, 45 years old or older, 50 years old or older, 55 years old or older, 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, 80 years old or older, 85 years old or older, 90 years old or older, 95 years old or older, 100 years old or older, or 105 years old or older,

In some embodiments of any of the methods described herein, the subject has been previously diagnosed or identified as having a disease associated with STING activity (e.g., a cancer, e.g., any of the exemplary types of cancer described herein). In some embodiments of any of the methods described herein, the subject is suspected of having a cancer (e.g., any of the exemplary cancers described herein). In some embodiments of any of the methods described herein, the subject is presenting with one or more (e.g., two, three, four, or five) symptoms of a cancer (e.g., any of the exemplary cancers described herein).

In some embodiments of any of the methods described herein, the subject is a participant in a clinical trial. In some embodiments of any of the methods described herein, the subject has been previously administered a pharmaceutical composition and the different pharmaceutical composition was determined not to be therapeutically effective.

The term “administration” or “administering” refers to a method of providing a dosage of a pharmaceutical composition or a compound to an invertebrate or a vertebrate, including a fish, a bird and a mammal (e.g., a human). In some aspects, administration is performed, e.g., orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, intralymphatic, topically, intraocularly, vaginally, rectally, intrathecally, or intracystically. The method of administration can depend on various factors, e.g., the site of the disease, the severity of the disease, and the components of the pharmaceutical composition.

The terms “treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread, or worsening of a disease, disorder or condition or of one or more symptoms thereof.

The phrase “an elevated level” or “an increased level” as used herein can be an increase or l. lx to lOOx, or higher (such as up to 200x) e.g., as compared to a reference level (e.g., any of the exemplary reference levels described herein). In some aspects, “an elevated level” or “an increased level” can be an increase of at least 1% (e.g., at least 2%, at least 4, at least 6%, at least 8%, at least 10 %, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least

160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 220%, at least

250%, at least 280%, at least 300%, at least 320%, at least 350%, at least 380%, at least

400%, at least 420%, at least 450%, at least 480%, at least 500%, at least 600%, at least

700%, at least 800%, at least 900%, or at least 1000%), e.g., as compared to a reference level (e.g., any of the exemplary reference levels described herein).

The phrase “a decreased level” as used herein can be a decrease of at least 1% (e.g., at least 2%, at least 4, at least 6%, at least 8%, at least 10 %, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, e.g., as compared to a reference level (e.g., any of the exemplary reference levels described herein).

The phrase “decreased ATM level” means a decrease in the level of ATM protein and/or ATM mRNA in a mammalian cell. For example, a decrease in the level of ATM can be a result of an ATM gene loss (at one or both alleles), a mutation in a regulatory region of an ATM gene that results in decreased transcription of an ATM gene as compared to the wildtype ATM gene, a mutation in an ATM gene that results in decreased translation of an ATM mRNA as compared to the wildtype ATM gene, and/or a mutation in an ATM gene that results in the production of an ATM protein that has decreased stability and/or half-life in a mammalian cell as compared to the wildtype ATM gene.

In some embodiments of any of the methods described herein can include determining the level of expression of an mRNA or a protein encoded by ATM. In some embodiments, a decreased level and/or activity of ATM can be determined by detection of a loss-of-function ATM mutation, an ATM gene deletion, one or more amino acid deletions in a protein encoded by an ATM gene, one or more amino acid insertions in a protein encoded by an ATM gene, and/or one or more amino acid substitutions in a protein encoded by an ATM gene.

The phrase “protein activity” (or “activity” of a particular protein) means one or more activities of the protein (e.g., enzymatic activity, localization activity, binding activity (e.g., binding another protein or binding a non-protein (e.g., a nucleic acid)). A decrease in activity of a protein in a mammalian cell can be, e.g., the result of an amino acid deletion in the protein, an amino acid insertion, or an amino acid substitution in the protein, e.g., as compared to the wildtype protein. In some cases, an increase in activity of a protein in a mammalian cell can be, e.g., the result of gene amplification or an activating amino acid substitution in the protein, e.g., as compared to the wildtype protein.

The phrase “ATM activity” means a direct activity of ATM in a mammalian cell (e.g., DNA damage-inducible protein kinase activity); or downstream signaling activity of ATM activity in a mammalian cell. For example, a decrease in ATM activity in a mammalian cell can be the result of, e.g., ATM gene loss (e.g., at one or both alleles), one or more nucleotide substitutions, deletions, and/or insertions in an ATM gene, one or more amino acid deletions, substitutions, insertions, truncations, or other modifications in an ATM protein, or one or more post-translational modifications to an ATM protein that alter its activity, localization, or function.

The term “increased STING pathway activity” means an increase in direct activity of STING in a mammalian cell (e.g., translocation of STING from the endoplasmic reticulum to the perinuclear area, or activation of TBK1 (TANK Binding Kinase 1); or an increase in upstream activity or a mutation (e.g., any of the exemplary mutations or single nucleotide polymorphisms described herein) in a mammalian cell that results in increased STING pathway activity in the mammalian cell (e.g., decreased level or activity of one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51 (e.g., as compared to any of the exemplary reference levels described herein) or increased level or activity of one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8, and MRE1 1 (e.g., as compared to any of the exemplary reference levels described herein).

A decreased level or activity of one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51 (e.g., in a cancer cell) can be caused by any mechanism.

In some embodiments, a decreased level or activity of BRCA1 can be a result of a frameshift mutation in a BRCA1 gene (e.g., an El 1 lGfs*3 frameshift insertion). In some embodiments, a decreased level or activity of BRCA1 can be a result of a BRCA1 gene loss (e.g., loss of one allele of BRCA1 or loss of both alleles of BRCA1). In some embodiments, a decreased level or activity of BRCA1 can be a result of one or more amino acid deletions in a protein encoded by a BRCA1 gene. In some embodiments, a decreased level or activity of BRCA1 in a can be a result of one or more inactivating amino acid substitutions in a protein encoded by a BRCA1 gene.

In some embodiments, a decreased level or activity of a BRCA2 gene can be result of a frameshift mutation in a BRCA2 gene (e.g., a N1784Kfs*3 frameshift insertion). In some embodiments, a decreased level or activity of BRCA2 can be a result of BRCA2 gene loss (e.g., loss of one allele of BRCA2 or loss of both alleles of BRCA2). In some embodiments, a decreased level or activity of BRCA2 can be a result of one or more amino acid deletions in a protein encoded by a BRCA2 gene. In some embodiments, a decreased level or activity of BRCA2 can be a result of one or more inactivating amino acid substitutions in a protein encoded by a BRCA2 gene.

In some embodiments, a decreased level or activity of SAMHD1 can be a result of one or more inactivating amino acid substitutions in a protein encoded by a SAMHD1 gene (e.g., a V133I amino acid substitution). In some embodiments, a decreased level or activity of SAMHD1 can be a result of gene loss (e.g., loss of one allele of SAMHD1 or loss of both alleles of SAMHD1). In some embodiments, a decreased level or activity of SAMHD1 can be a result of one or more amino acid deletions in a protein encoded by a SAMHD1 gene.

In some embodiments, a decreased level or activity of DNASE2 can be a result of one or more inactivating mutations in a protein encoded by a DNASE2 gene (e.g., a R314W amino acid substitution). In some embodiments, a decreased level or activity of DNASE2 can be a result of DNASE2 gene loss (e.g., loss of one allele of DNASE2 or loss of both alleles of DNASE2). In some embodiments, a decreased level or activity of DNASE2 can be a result of one or more amino acid deletions in a protein encoded by a DNASE2 gene.

In some embodiments, a decreased level or activity of BLM can be a result of a frameshift mutation in a BLM gene (e.g., a N515Mfs*16 frameshift deletion). In some embodiments, a decreased level or activity of BLM can be a result of BLM gene loss (e.g., loss of one allele of BLM or loss of both alleles of BLM). In some embodiments, a decreased level or activity of BLM can be a result of one or more amino acid deletions in a protein encoded by a BLM gene. In some embodiments, a decreased level or activity of BLM can be a result of one or more inactivating amino acid substitutions in a protein encoded by a BLM gene.

In some embodiments, a decreased level or activity of PARP1 can be a result of a frameshift mutation in a PARP1 gene (e.g., a S507Afs*17 frameshift deletion). In some embodiments, a decreased level or activity of PARP1 can be a result of gene loss (e.g., loss of one allele of PARP1 or loss of both alleles of PARP1). In some embodiments, a decreased level or activity of PARP1 can be a result of one or more amino acid deletions in a protein encoded by a PARP1 gene. In some embodiments, a decreased level or activity of PARP1 can be a result of one or more inactivating amino acid substitutions in a protein encoded by a PARP1 gene.

In some embodiments, a decreased level or activity of RPA1 can be a result of a mutation that results in aberrant RPA mRNA splicing (e.g., a X12 splice mutation). In some embodiments, a decreased level or activity of RPA1 can be a result of RPA1 gene loss (e.g., loss of one allele of RPA1 or loss of both alleles of RPA1). In some embodiments, a decreased level or activity of RPA1 can be a result of one or more amino acid deletions in a protein encoded by a RPA1 gene. In some embodiments, a decreased level or activity of RPA1 can be a result of one or more inactivating amino acid substitutions in a protein encoded by a RPA1 gene.

In some embodiments, a decreased level or activity of RAD51 can be a result of one or more inactivating mutations in a protein encoded by a RAD51 gene (e.g., a R254* mutation). In some embodiments, a decreased level or activity of RAD51 can be a result of RAD51 gene loss (e.g., loss of one allele of RAD51 or loss of both alleles of RAD51). In some embodiments, a decreased level or activity of RAD51 can be a result of one or more amino acid deletions in a protein encoded by a RAD51 gene.

An increased level or activity of one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8, or MRE11 (e.g., in a cancer cell) can be caused by any mechanism.

In some embodiments, an increased level or activity of MUS81 can be a result of MUS81 gene amplification. In some embodiments, an increase dlevel or activity of MUS81 can be a result of one or more activating amino acid substitutions in a protein encoded by a MUS81 gene.

In some embodiments, an increased level or activity of IFI16 can be a result of IFI16 gene amplification. In some embodiments, an increased level or activity of IFI16 can be a result of one or more activating amino acid substitutions in a protein encoded by an IFI16 gene.

In some embodiments, an increased level or activity of cGAS can be a result of cGAS gene amplification. In some embodiments, an increased level or activity of cGAS can be a result of one or more activating amino acid substitutions in a protein encoded by a cGAS gene.

In some embodiments, an increased level or activity of DDX41 can be a result of DDX41 gene amplification. In some embodiments, an increased level or activity of DDX41 can be a result of one or more activating amino acid substitutions in a protein encoded by a DDX41 gene.

In some embodiments, an increased level or activity of EXO 1 can be a result of EXO1 gene amplification. In some embodiments, an increased level or activity of EXO 1 can be a result of one or more activating amino acid substitutions in a protein encoded by an EXO1 gene. In some embodiments, an increased level or activity of DNA2 can be a result of DNA2 gene amplification. In some embodiments, an increased level or activity of DNA2 can be a result of one or more activating amino acid substitutions in a protein encoded by a DNA2 gene. In some embodiments, an increased level or activity of RBBP8 (also called CtIP) can be a result of RBBP8 gene amplification. In some embodiments, an increased level or activity of RBBP8 can be a result of one or more activating amino acid substitutions in a protein encoded by a RBBP8 gene.

In some embodiments, an increased level or activity of MRE11 can be a result of MRE11 gene amplification. In some embodiments, an increased level or activity of MRE11 can be a result of one or more activating amino acid substitutions in a protein encoded by a MRE11 gene.

Non-limiting examples of human protein and human cDNA sequences for STING, TREX1, BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, RAD51, MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE11 are shown below (SEQ ID NOs.: 1-89). It will be understood that other natural variants of these sequences can exist, and it will be understood that the name of a gene can be used to refer to the gene or to its protein product.

Some embodiments of any of the methods described herein include determining the level of expression of a mRNA or a protein encoded by of one or more of STING, TREX1, BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, RAD51, MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE11. In some examples of any of the methods described herein, increased STING or cGAS signaling activity can include, e.g., detecting a decreased level of a mRNA or a protein encoded by one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51, and/or detecting an increased level of a mRNA or protein encoded by one or more of STING, MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE11 in a mammalian cell (e.g., as compared to any of the exemplary reference levels described herein).

Some embodiments of any of the methods described herein, an increased cGAS/STING signaling activity can be determined by detecting of a gain-of-function mutation (e.g., a gene amplification or one or more activating amino acid substitutions in a protein encoded by one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), and MRE1); a gene deletion of one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, andRAD51; one or more amino acid deletions in a protein encoded by one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51; one or more inactivating amino acid mutations in a protein encoded by one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, or RAD51; or a frameshift mutation in one or more of BRCA1, BRCA2, SAMHD1, DNASE2, BLM, PARP1, RPA1, and RAD51.

Methods of detecting a level of each of these exemplary cGAS/STING signaling pathway activities are described herein. Additional examples of cGAS/STING signaling pathway activities are known in the art, as well as methods for detecting a level of the same.

As used herein, “gain-of-function mutation” refers to one or more nucleotide substitutions, deletions, and/or insertions in a gene that results in the production of a protein encoded by the gene that has one or more increased activities in a mammalian cell as compared to the version of the protein encoded by the corresponding wildtype gene. In some embodiments, a gain-of-function mutation can be a gene amplification or one or more activating amino acid substitutions in a protein encoded by one or more of MUS81, IFI16, cGAS, DDX41, EXO1, DNA2, RBBP8 (CtIP), STING, and MRE1.

As used herein, “loss-of-function mutation” refers to one or more nucleotide substitutions, deletions, and/or insertions in a gene that results in: a decrease in the level of expression of the encoded protein as compared to the level of the expression by the corresponding wildtype gene, and/or the expression of a protein encoded gene that has one or more decreased activities in a mammalian cell as compared to the version of the protein encoded by the corresponding wildtype gene. In some embodiments, a loss-of-function mutation can be a gene deletion, one or more amino acid deletions in a protein encoded by a gene, or one or more inactivating amino acid substitutions in a protein encoded by a gene.

The terms “hydrogen” and “H” are used interchangeably herein.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Cl-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

The term “carbocyclic ring” as used herein includes an aromatic or nonaromatic cyclic hydrocarbon group having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. Examples of carbocyclic rings include fivemembered, six membered, and seven-membered carbocyclic rings.

The term “heterocyclic ring” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1- 3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms ofN, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclic rings include five-membered, six membered, and seven-membered heterocyclic rings.

The term “cycloalkyl” as used herein includes an aromatic or nonaromatic cyclic hydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, wherein the cycloalkyl group which may be optionally substituted. Examples of cycloalkyls include five membered, six-membered, and seven-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term “heterocycloalkyl” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system radical having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1- 9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkyls include five-membered, six-membered, and seven-membered heterocyclic rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

The term “hydroxy” refers to an OH group.

The term “amino” refers to an NH2 group.

The term “oxo” refers to O. By way of example, substitution of a CH2 a group with oxo gives a C=O group.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

DETAILED DESCRIPTION

The present invention is based on the discovery that cancer cells having decreased ATM level and/or activity are more sensitive to treatment with a STING antagonist or cGAS inhibitor. In view of these discoveries, provided herein are methods of treating a subject in need thereof with a treatment including a STING antagonist or cGAS inhibitor, methods of selecting a treatment for a subject in need thereof, where the treatment includes a STING antagonist or cGAS inhibitor, methods of selecting a subject for treatment with a STING antagonist or cGAS inhibitor, methods of selecting a subject for participation in a clinical trial with a STING antagonist or cGAS inhibitor, and methods of predicting a subject’s responsiveness to a STING antagonist or cGAS inhibitor (e.g., a compound of any one of Formulas I-XXIV or Formulas M1-M6 or a compound shown in any one of Tables C1-C2)

Non-liming aspects of these methods are described below, and can be used in any combination without limitation. Additional aspects of these methods are known in the art.

ATM

Ataxia-telangiectasia mutated kinase (ATM) is a DNA damage-inducible protein kinase that is recruited and activated by DNA double-strand breaks. ATM phosphorylates substrates (e.g., p53, CHK2, BRCA1, NBS1, and H2AX) participating in DNA damage response initiating activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair, or apoptosis.

The ATM gene expresses the ATM protein that is located primarily in the nucleus of cells, where it helps control the rate of cell growth and division. The ATM protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. DNA can be damaged by agents such as toxic chemicals or radiation, and breaks in DNA strands also occur naturally when chromosomes exchange genetic material during cell division. The ATM protein coordinates DNA repair by activating enzymes that fix the broken strands, while efficient repair of damaged DNA strands helps maintain the stability of the cell’s genetic information.

ATM being a central component of the DNA repair machinery, dysfunction in the ATM gene results in non-canonical activation of STING. It has been shown that ATM plays an important role in the assembly of DNA damage-induced STING complex, wherein the molecular mechanism of double-strand break recognition by ATM and the subsequent phosphorylation of p53 provide a molecular link between DNA damage and STING complex formation (see, e.g., Dunphy et al., Molecular Cell 71 :745-760, 2018). Furthermore, loss of ATM activity in cells leads to accumulation of cytosolic DNA and results in activation of the cGAS-STING pathway and cytokine production.

A decreased level or activity of ATM can be caused by any mechanism. Several mutations have been linked to inactivation of ATM. For example, mutations in the MRN subunit NBS1 and/or subunit Mrel l can result in decreased ATM activation. In some embodiments, heterozygous ATM mutations (e.g., germline ATM missense mutation 7271T>G, or IVD10-6T>G) can result in a decreased level of ATM activity (e.g., Bernstein et al., Br. J. Cancer 89(8): 1513-1516, 2003). In some embodiments, amino acid substitutions in an ATM protein (e.g., G138R, V245A, or R2912K) can result in a decrease in one or more activities of an ATM protein (see, e.g., Squatrito et al., Cancer Cell 18(6), 2010). Additional examples of mutations in an ATM gene that result in a decrease in the level and/or activity of ATM include 8307G>A, 8 MOOT, 1339OT, 1240OT, 9170G>C, and 8711A>G (see, e.g., Gilad et al., Human Molecular Genetics 5(4):433, 1996).

In some embodiments, a decreased level and/or activity of ATM can be a result of a deletion mutation in an ATM gene (e.g., 8578del3 deletion). In some embodiments, a decreased level and/or activity of ATM can be a result of an insertion mutation in an ATM gene (e.g., 5319ins9 insertion). In some embodiments, a decreased level and/or activity of ATM can be a result of ATM gene loss (e.g., loss of one allele of ATM or loss of both alleles of ATM). In some embodiments, a decreased level and/or activity of ATM can be a result of one or more amino acid deletions in a protein encoded by an ATM gene. In some embodiments, a decreased level and/or activity of ATM can be a result of one or more inactivating amino acid substitutions in a protein encoded by an ATM gene. In some embodiments, a decreased level and/or activity of ATM can be a result of one or more amino acid insertions in a protein encoded by an ATM gene.

In some embodiments, a decrease in the level of ATM can be the result of mutation in a regulatory region of an ATM gene (e.g., that results in a decrease in transcription of the ATM gene and/or a decrease in translation of an mRNA encoded by the ATM gene).

In some embodiments, a mutation (e.g., any of the exemplary types of mutations described herein) is present in both alleles of the ATM gene in the cancer cell. In some embodiments, a mutation (e.g., any of the exemplary types of mutations described herein) is present in one allele of the ATM gene in the cancer cell. In some embodiments, a mutation in an ATM gene results the production of a truncated and non-functional version of an ATM protein.

A sequence of an exemplary wildtype human ATM protein is SEQ ID NO: 90. A sequence of an exemplary wildtype human ATM cDNA is SEQ ID NO: 91.

Methods of Treating

Provided herein are methods of treating a subject (e.g., any of the exemplary subjects described herein) in need thereof that include: (a) identifying a subject having a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease of 1% to about 99%, 1% to about 95%, 1% to about 90%, 1% to about 80%, 1% to about 70%, 1% to about 60%, 1% to about 50%, 1% to about 40%, 1% to about 30%, 1% to about 20%, 1% to about 10%, about 5% to about 99%, about 5% to about 90%, about 5% to about 80%, about 5% to about 70%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 5% to about 10%, about 10% to about 99%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 99%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 99%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 99%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 99%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 99%, about 60% to about 90%, about 60% to about 80%, about 60% to about 70%, about 70% to about 99%, about 70% to about 90%, about 70% to about 80%, about 80% to about 99%, about 80% to about 90%, or about 90% to about 99%) or any subranges of this range described herein) (e.g., as compared to a reference level); and (b) administering a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitors described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects described herein) in need thereof that include: administering a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitors described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample.

In some embodiments, the subject is identified as having a cancer cell having decreased ATM level. In some embodiments, the ATM level is a level of ATM protein in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level includes detecting a decreased level of ATM protein in the cancer cell. In some embodiments, the ATM level is a level of ATM mRNA in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level comprises detecting a decreased level of ATM mRNA in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of ATM gene loss in the cancer cell. In some embodiments, the ATM gene loss is loss of one allele of the ATM gene. In some embodiments, the ATM gene loss is loss of both alleles of the ATM gene. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting ATM gene loss in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of one or more amino acid deletions, insertions, or post-translational modifications of a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting one or more amino acid deletions, insertions, or post-translational modifications in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the decreased ATM level and/or activity is a result of one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM expression and/or activity comprises detecting one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell.

In some embodiments, the subject is further identified as having an elevated level of cGAMP in a serum or tumor sample obtained from the subject (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level). In some embodiments, the subject is further identified as having a cancer cell having increased cGAS/STING signaling pathway activity (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level).

In some embodiments, the subject has been diagnosed or identified as having a cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, kidney renal papillary cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

In some embodiments of any of the methods described herein, the STING antagonist or cGAS inhibitor is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, a cyclic dinucleotide, or a ribozyme). In some embodiments of any of the methods described herein, the STING antagonist or cGAS inhibitor is any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, with the proviso that in embodiments related to a gain of function mutation in STING, a cGAS inhibitor is not employed in a method described herein.

In some embodiments of any of the methods of treatment described herein, the method can result in a decreased risk (e.g., a 1% to a 99% decrease, or any of the subranges of this range described herein) of developing a comorbidity in the subject (e.g., as compared to the risk of developing a comorbidity in a subject having cancer cells having a similar decreased ATM level and/or activity and/or increased cGAS/STING signaling pathway activity, but administered a different treatment or a placebo).

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Methods of Selecting a Treatment for a Subject

Provided herein are methods of selecting a treatment for a subject (e.g., any of the exemplary subjects described herein) in need thereof that include: (a) identifying a subject having a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitor described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of selecting a treatment for a subject (e.g., any of the exemplary subjects described herein) in need thereof that include: selecting a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitors described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample.

In some embodiments, the subject is identified as having a cancer cell having decreased ATM level. In some embodiments, the ATM level is a level of ATM protein in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level includes detecting a decreased level of ATM protein in the cancer cell. In some embodiments, the ATM level is a level of ATM mRNA in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level comprises detecting a decreased level of ATM mRNA in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of ATM gene loss in the cancer cell. In some embodiments, the ATM gene loss is loss of one allele of the ATM gene. In some embodiments, the ATM gene loss is loss of both alleles of the ATM gene. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting ATM gene loss in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of one or more amino acid deletions, insertions, or post-translational modifications of a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting one or more amino acid deletions, insertions, or post-translational modifications in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the decreased ATM level and/or activity is a result of one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM expression and/or activity comprises detecting one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell.

In some embodiments, the subject is further identified as having an elevated level of cGAMP in a serum or tumor sample obtained from the subject (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level). In some embodiments, the subject is further identified as having a cancer cell having increased cGAS/STING signaling pathway activity (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level).

In some embodiments, the subject has been diagnosed or identified as having a cancer. In some embodiments, the cancer is selected from the group consisting of: renal clear cell carcinoma, kidney renal papillary cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of: renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer. In some embodiments, the methods further comprise administering the selected treatment to the subject.

In some embodiments of any of the methods described herein, the STING antagonist or cGAS inhibitor is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, a cyclic dinucleotide, or a ribozyme). In some embodiments of any of the methods described herein, the STING antagonist or cGAS inhibitor is any of the STING antagonists or cGAS inhibitors described herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments including a gain of function mutation in STING, a cGAS inhibitor is not employed in a method of the present disclosure.

Some embodiments of any of the methods described herein can further include recording the selected treatment in the subject’s clinical record (e.g., a computer readable medium). Some embodiments of any of the methods described herein can further include administering one or more doses (e.g., at least two, at least four, at least six, at least eight, at least ten doses) of the selected treatment to the identified subject.

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Methods of Selecting a Subject for Treatment

Also provided herein are methods of selecting a subject for treatment that include: (a) identifying a subject (e.g., any of the subjects described herein) having a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g, a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample; and (b) selecting an identified subj ect for treatment with a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitors described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of selecting a subject for treatment that include selecting a subject (e.g., any of the subjects described herein) identified as having a cell

T1 (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease to about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample, for treatment with a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitor described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments, the subject is identified as having a cancer cell having decreased ATM level. In some embodiments, the ATM level is a level of ATM protein in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level includes detecting a decreased level of ATM protein in the cancer cell. In some embodiments, the ATM level is a level of ATM mRNA in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level comprises detecting a decreased level of ATM mRNA in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of ATM gene loss in the cancer cell. In some embodiments, the ATM gene loss is loss of one allele of the ATM gene. In some embodiments, the ATM gene loss is loss of both alleles of the ATM gene. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting ATM gene loss in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of one or more amino acid deletions, insertions, or post-translational modifications of a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting one or more amino acid deletions, insertions, or post-translational modifications in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the decreased ATM level and/or activity is a result of one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM expression and/or activity comprises detecting one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell.

In some embodiments, the subject is further identified as having an elevated level of cGAMP in a serum or tumor sample obtained from the subject (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level). In some embodiments, the subject is further identified as having a cancer cell having increased cGAS/STING signaling pathway activity (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level).

In some embodiments, the subject has been diagnosed or identified as having a cancer. In some embodiments, the cancer is selected from the group consisting of: renal clear cell carcinoma, kidney renal papillary cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of: renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

In some embodiments of any of the methods described herein, the STING antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, a cyclic dinucleotide, or a ribozyme). In some embodiments of any of the methods described herein, the STING antagonist or cGAS inhibitor is any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Methods of Selecting a Subject For Participation in a Clinical Trial

Provided herein are methods of selecting a subject (e.g., any of the exemplary subjects described herein) for participation in a clinical trial that include: (a) identifying a subject having a cancer cell having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample; and (b) selecting the identified subject for participation in a clinical trial that comprises administration of a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitors described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of selecting a subject (e.g., any of the exemplary subjects described herein) for participation in a clinical trial that include: selecting a subject identified as having a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample for participation in a clinical trial that comprises administration of a treatment comprising a therapeutically effective amount of a STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitors described herein) or a pharmaceutically acceptable salt, solvate, or cocrystal thereof.

In some embodiments, the subject is identified as having a cancer cell having decreased ATM level. In some embodiments, the ATM level is a level of ATM protein in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level includes detecting a decreased level of ATM protein in the cancer cell. In some embodiments, the ATM level is a level of ATM mRNA in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level comprises detecting a decreased level of ATM mRNA in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of ATM gene loss in the cancer cell. In some embodiments, the ATM gene loss is loss of one allele of the ATM gene. In some embodiments, the ATM gene loss is loss of both alleles of the ATM gene. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting ATM gene loss in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of one or more amino acid deletions, insertions, or post-translational modifications of a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting one or more amino acid deletions, insertions, or post-translational modifications in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the decreased ATM level and/or activity is a result of one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM expression and/or activity comprises detecting one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell.

In some embodiments, the subject is further identified as having an elevated level of cGAMP in a serum or tumor sample from the subject (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level). In some embodiments, the subject is further identified as having a cancer cell having increased cGAS/STING signaling pathway activity (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level).

In some embodiments, the subject has been diagnosed or identified as having a cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, kidney renal papillary cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

In some embodiments of any of the methods described herein, the STING antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, a cyclic dinucleotide, or a ribozyme). In some embodiments of any of the methods described herein, the STING antagonist or cGAS inhibitor is any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Additional exemplary aspects that can be used or incorporated in these methods are described herein. Methods of Predicting a Subject’s Responsiveness to a STING antagonist or cGAS inhibitor

Provided herein are methods of predicting a subject’s (e.g., any of the exemplary subjects described herein) responsiveness to a compound of any one of Formulas I-XXIV or Formulas M1-M6 that include: (a) determining that a subject has a cancer cell having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample; and (b) identifying that the subject determined to have decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample, in step (a) has an increased likelihood of being responsive to treatment with a compound of any one of Formulas I-XXIV or Formulas M1-M6.

Provided herein are methods of predicting a subject’s (e.g., any of the exemplary subjects described herein) responsiveness to a STING antagonist or cGAS inhibitor that include: (a) determining that a subject has a cancer cell having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample; and (b) identifying that the subject determined to have decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample, in step (a) has an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor.

Also provided herein are methods of predicting a subject’s (e.g., any of the exemplary subjects described herein) responsiveness to a compound of any one of Formulas I-XXIV or Formulas M1-M6 that include: identifying a subject determined to have a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample, as having an increased likelihood of being responsive to treatment with a compound of any one of Formulas I-XXIV or Formulas M1-M6. Also provided herein are methods of predicting a subject’s (e.g., any of the exemplary subjects described herein) responsiveness to a STING antagonist or a cGAS inhibitor that include: identifying a subject determined to have a cell (e.g., a cancer cell) having decreased ATM level and/or activity (e.g., a decrease of about 1% to about 99%, or any subranges of this range described herein) (e.g., as compared to a reference level) in a tumor sample, as having an increased likelihood of being responsive to treatment with a STING antagonist or a cGAS inhibitor.

In some embodiments, the subject is identified as having a cancer cell having decreased ATM level. In some embodiments, the ATM level is a level of ATM protein in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level includes detecting a decreased level of ATM protein in the cancer cell. In some embodiments, the ATM level is a level of ATM mRNA in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level comprises detecting a decreased level of ATM mRNA in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of ATM gene loss in the cancer cell. In some embodiments, the ATM gene loss is loss of one allele of the ATM gene. In some embodiments, the ATM gene loss is loss of both alleles of the ATM gene. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting ATM gene loss in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of one or more amino acid deletions, insertions, or post-translational modifications of a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting one or more amino acid deletions, insertions, or post-translational modifications in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the decreased ATM level and/or activity is a result of one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM expression and/or activity comprises detecting one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell.

In some embodiments, the subject is further identified as having an elevated level of cGAMP in a serum or tumor sample from the subject (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level). In some embodiments, the subject is further identified as having a cancer cell having increased cGAS/STING signaling pathway activity (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level).

In some embodiments, the subject has been diagnosed or identified as having a cancer. In some embodiments, the cancer is selected from the group consisting of: renal clear cell carcinoma, kidney renal papillary cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer. In some embodiments, the cancer is selected from the group consisting of: renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer.

In some embodiments, the methods further comprise administering a therapeutically effective amount of a STING antagonist or cGAS inhibitor to a subject identified as having an increased likelihood of being responsive to treatment with a STING antagonist or cGAS inhibitor.

In some embodiments of any of the methods described herein, the STING antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, a cyclic dinucleotide, or a ribozyme). In some embodiments of any of the methods described herein, the STING antagonist or cGAS inhibitor is any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Indications In some embodiments, methods for treating a subject having condition, disease or disorder in which an increase in cGAS/STING signaling activity and/or a decrease in ATM level and/or activity contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder are provided, comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). In some embodiments of any of the methods described herein, the subject can have, or be identified or diagnosed as having, any of the conditions, diseases, or disorders in which an increase in cGAS/STING signaling activity and/or a decrease in ATM level and/or activity contributes to the pathology and/or symptoms and/or progression of the condition, disease, or disorder. In some embodiments of any of the methods described herein, the subject can be suspected of having or present with one or more symptoms of any of the conditions, diseases, or disorders described herein.

In some embodiments, the condition, disease or disorder is a cancer (e.g., renal clear cell carcinoma, kidney renal papillary cell carcinoma, chromophobe renal cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, osteosarcoma, and skin cancer). In some embodiments, the condition, disease or disorder is a cancer (e.g., renal clear cell carcinoma, uveal melanoma, tongue squamous cell carcinoma, breast cancer, and skin cancer).

Combination Therapy

This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the STING antagonist or cGAS inhibitor (e.g., any of the STING antagonists or cGAS inhibitors described herein or known in the art).

In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the STING antagonist or cGAS inhibitor (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the STING antagonist or cGAS inhibitor. By way of example, the second therapeutic agent or regimen and the STING antagonist or cGAS inhibitor are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the STING antagonist or cGAS inhibitor are provided to the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the STING antagonist or cGAS inhibitor (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein include the step of identifying a subject (e.g., a patient) in need of treatment as having a cell (e.g., a cancer cell) having decreased ATM level and/or activity.

In some embodiments, the methods described herein further include the step of further identifying a subject (e.g., a patient) in need of treatment as having a cell (e.g., a cancer cell) having increased cGAS/STING signaling pathway activity (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level). In some embodiments, the methods described herein further include identifying a subject (e.g., a patient) in need of treatment as having an elevated level of cGAMP in a serum or a tumor sample (e.g., an increase of between 1% and 1000%, or any of the subranges of this range described herein) (e.g., as compared to a reference level). In some embodiments, the subject is identified as having a cancer cell having decreased ATM level. In some embodiments, the ATM level is a level of ATM protein in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level includes detecting a decreased level of ATM protein in the cancer cell. In some embodiments, the ATM level is a level of ATM mRNA in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having a decreased ATM level comprises detecting a decreased level of ATM mRNA in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of ATM gene loss in the cancer cell. In some embodiments, the ATM gene loss is loss of one allele of the ATM gene. In some embodiments, the ATM gene loss is loss of both alleles of the ATM gene. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting ATM gene loss in the cancer cell.

In some embodiments, the decreased ATM level and/or activity is a result of one or more amino acid deletions, insertions, or post-translational modifications of a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM level and/or activity comprises detecting one or more amino acid deletions, insertions, or post-translational modifications in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the decreased ATM level and/or activity is a result of one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell. In some embodiments, the identification of the subject as having a cancer cell having decreased ATM expression and/or activity comprises detecting one or more inactivating amino acid substitutions in a protein encoded by an ATM gene in the cancer cell.

Methods of Detecting the Level of ATM activity and/or Expression

In some embodiments of any of the methods described herein, a mammalian cell having decreased level and/or activity of ATM can be identified by, e.g., detecting the presence of a mutation in an ATM gene (e.g., any of the exemplary mutations in an ATM gene described herein, such as an ATM gene loss (e.g., loss of one or both alleles of ATM), an amino acid deletion in the protein encoded by an ATM gene, an amino acid insertion in the protein encoded by an ATM gene, or an inactivating amino acid substitution in a protein encoded by an ATM gene). Non-limiting examples of assays that can be used to determine the level of the presence of any of these mutations (e.g., any of the mutations described herein) include Southern blot analysis, Northern blot analysis, mass spectrometry, UV absorbance, lab-on-a-chip, microfluidics, gene chip, intercalating dyes (e.g., ethidium bromide), gel electrophoresis, restriction digestion and electrophoresis, and sequencing (e.g., using any of the wide variety of sequencing methods described herein or known in the art), including polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis.

For example, the detection of genomic DNA can include detection of the presence of one or more unique sequences found in genomic DNA (e.g., human genomic DNA) (e.g., satellite DNA sequences present in centromeres or heterochromatin, minisatellite sequences, microsatellite sequences, the sequence of a transposable element, a telomere sequence, a specific sequence (e.g., 250 base pairs to about 300 base pairs) containing one or more SNPs, or a specific sequence encoding a gene). Detection can be performed using labeled probes (e.g., fluorophore-, radioisotope-, enzyme-, quencher-, and enzyme-labeled probes), e.g., by hybridizing labeled probes to the genomic DNA present in the isolated genomic DNA sample or the control sample (e.g., in an electrophoretic gel) or hybridizing the labeled probes to the products of a PCR assay (e.g., a real-time PCR assay) or an assay that includes a PCR assay that utilized genomic DNA in the isolated genomic DNA test sample or the control sample as the template. Non-limiting examples of methods that can be used to generate probes include nick translation, random oligo primed synthesis, and end labeling.

A variety of assays for determining the genotype of a gene are known in the art. Non-limiting examples of such assays (which can be used in any of the methods described herein) include: dynamic allele-specific hybridization (see, e.g., Howell et al., Nature Biotechnol. 17:87-88, 1999), molecular beacon assays (see, e.g., Marras et al., “Genotyping Single Nucleotide Polymorphisms with Molecular Beacons,” In Kwok (Ed.), Single Nucleotide Polymorphisms: Methods and Protocols, Humana Press, Inc., Totowa, NJ, Vol. 212, pp. 111-128, 2003), microarrays (see, e.g., Affymetrix Human SNP 5.0 GeneChip), restriction fragment length polymorphism (RFLP) (see, e.g., Ota et al., Nature Protocols 2:2857-2864, 2007), PCR-based assays (e.g., tetraprimer ARMS -PCR (see, e.g., Zhang et al., Pios One 8:e62126, 2013), real-time PCR, allele-specific PCR (see, e.g., Gaudet et al., Methods Mol. Biol. 578:415-424, 2009), and TaqMan Assay SNP Genotyping (see, e.g., Woodward, Methods Mol. Biol. 1145:67-74, 2014, and TaqMan®Open Array® Genotyping Plates from Life Technologies)), Flap endonuclease assays (also called Invader assays) (see, e.g., Olivier et al., Mutat. Res. 573 : 103-110, 2005), oligonucleotide ligation assays (see, e.g., Bruse et al., Biotechniques 45:559-571, 2008), single strand conformational polymorphism assays (see, e.g., Tahira et al., Human Mutat. 26:69-77, 2005), temperature gradient gel electrophoresis (see, e.g., Jones et al., “Temporal Temperature Gradient Electrophoresis for Detection of Single Nucleotide Polymorphisms,” in Single Nucleotide Polymophisms: Methods and Protocols, Volume 578, pp. 153-165, 2008) or temperature gradient capillary electrophoresis, denaturing high performance liquid chromatography (see, e.g., Yu et al., J. Clin. Pathol. 58:479-485, 2005), high-resolution melting of an amplified sequence containing the SNP (see, e.g., Wittwer et al., Clinical Chemistry 49:853-860, 2003), or sequencing (e.g., Maxam-Gilbert sequencing, chain-termination methods, shotgun sequencing, bridge PCR, and nextgeneration sequencing methods (e.g., massively parallel signature sequencing, polony sequencing, 454 pyrosequencing, Illumina (Solexa) sequencing, SOLiD sequencing, Ion Torrent semiconductor sequence, DNA nanoball sequencing, heliscope single molecule sequencing, and single molecule real-time sequencing). Additional details and a summary of various next-generation sequencing methods are described in Koboldt et al., Cell 155:27-38, 2013.

In some embodiments of any of the methods described herein, the genotyping of a gene includes a PCR assay (e.g., a real-time PCR-assay) (with or without a prior preamplification step (e.g., any of the pre-amplification methods described herein)). In some embodiments of any of the methods described herein the genotyping can be performed using TaqMan®-based sequencing (e.g., TaqMan®-based OpenArray® sequencing, e.g., high throughput TaqMan®-based Open Array® sequencing) (with or without a prior preamplification step (e.g., any of the pre-amplification methods described herein)).

In some embodiments of any of the methods described herein, the level of the protein or mRNA can be detected in a biological sample including blood, serum, exosomes, plasma, tissue, urine, feces, sputum, and cerebrospinal fluid.

Determination of a level of an ATM protein can be performed using commercially available assays (e.g., RayBiotch, Novus Bio, LSBio, Rocky Mountain Diagnostics). Additional methods for determining a level of an ATM protein can be performed using immunoblotting and proteomics techniques.

Non-limiting assays for ATM kinase activity are described in, e.g., Adams et al., Methods Mol. Biol. 1599:43-56, 2017; and Nyati et al., Methods Mol. Biol. 1596: 131-145, 2017. Additional methods for determining ATM kinase activity are known in the art.

Methods of Detecting the Level of cGAS/STING Signaling Pathway Activity and/or Expression

In some embodiments of any of the methods described herein, the cGAS/STING signaling pathway activity is the secretion of a type I IFN or a type III IFN. In some embodiments of any of the methods described herein, the cGAS/STING signaling pathway activity is the secretion of IFN-a. In some embodiments of any of the methods described herein, the cGAS/STING signaling pathway activity is the secretion of IFN-p. Nonlimiting examples of methods that can be used to detect the secretion of IFN-a and IFN-P include immunohistochemistry, immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, and immunofluorescent assay.

Non-limiting methods of detecting cGAMP in serum or tissue include immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, and immunofluorescent assay) a mass spectrometry.

In some embodiments of any of the methods described herein, the cGAS/STING signaling pathway activity can be the level and/or activity of an upstream activator in the cGAS/STING signaling pathway (e.g., the level of one or more (e.g., two, three, four, five, or six) of MUS81 mRNA, MUS81 protein, IFI16 mRNA, IFI16 protein, cGAS mRNA, cGAS protein, DDX41 mRNA, DDX41 protein, EXO1 mRNA, EXO1 protein, DNA2 mRNA, DNA2 protein, RBBP8 mRNA, RBBP8 protein, MRE11 mRNA, or MRE11 protein in a mammalian cell (e.g., a mammalian cell obtained from a subject). In some embodiments of any of the methods described herein, the cGAS/STING signaling pathway activity can be determined by detecting the level and/or activity of an upstream suppressor of the cGAS/STING signaling pathway (e.g., the level of one or more (e.g., two, three, four, five, or six) of BRCA1 mRNA, BRCA1 protein, BRCA2 mRNA, BRCA2 protein, SAMHD1 mRNA, SAMHD1 protein, DNASE2 mRNA, DNASE2 protein, BLM mRNA, BLM protein, PARP1 mRNA, PARP1 protein, RPA1 mRNA, RPA1 protein, RAD51 mRNA, or RAD51 protein in a mammalian cell (e.g., a mammalian cell obtained from a subject).

Non-limiting assays that can be used to determine the level and/or activity of an upstream activator or upstream suppressor of the STING pathway include: Southern blot analysis, Northern blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, microarray analysis, immunohistochemistry, immunoassays, e.g., enzyme- linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluorescent assay, mass spectrometry, immunoblot (Western blot), RIA, and flow cytometry.

In some embodiments of any of the methods described herein, a mammalian cell having an increased level of cGAS/STING signaling pathway activity can be identified by detecting the presence of one of more of the following the mammalian cell: a gain-of- function mutation in a cGAS/STING signaling pathway gene (e.g., a BRCA1 protein having a El l lGfs*3 frameshift insertion, numbered according to SEQ ID NO: 15, a BRCA1 protein having aN1784Kfs*3 frameshift insertion numbered according to SEQ ID NO: 25, a SAMHD1 protein having a V133I amino acid substitution numbered according to SEQ ID NO: 27, a DNASE2 protein having R314W amino acid substitution numbered according to SEQ ID NO: 33, a BLM protein having a N515Mfs*16 frameshift deletion numbered according to SEQ ID NO: 37, a PARP1 protein having a S507Afs* 17 frameshift deletion numbered according to SEQ ID NO: 43, a RPA1 mRNA splicing having a X12 splice mutation, or a RAD51 protein having R254* amino acid substitution numbered according to SEQ ID NO: 51).

Non-limiting examples of assays that can be used to determine the level of the presence of any of these mutations (e.g., any of the mutations described herein) include Southern blot analysis, Northern blot analysis, mass spectrometry, UV absorbance, lab-on- a-chip, microfluidics, gene chip, intercalating dyes (e.g., ethidium bromide), gel electrophoresis, restriction digestion and electrophoresis, and sequencing (e.g., using any of the wide variety of sequencing methods described herein or known in the art), including polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis.

For example, the detection of genomic DNA can include detection of the presence of one or more unique sequences found in genomic DNA (e.g., human genomic DNA) (e.g., satellite DNA sequences present in centromeres or heterochromatin, minisatellite sequences, microsatellite sequences, the sequence of a transposable element, a telomere sequence, a specific sequence (e.g., 250 base pairs to about 300 base pairs) containing one or more SNPs, or a specific sequence encoding a gene). Detection can be performed using labeled probes (e.g., fluorophore-, radioisotope-, enzyme-, quencher-, and enzyme-labeled probes), e.g., by hybridizing labeled probes to the genomic DNA present in the isolated genomic DNA sample or the control sample (e.g., in an electrophoretic gel) or hybridizing the labeled probes to the products of a PCR assay (e.g., a real-time PCR assay) or an assay that includes a PCR assay that utilized genomic DNA in the isolated genomic DNA test sample or the control sample as the template. Non-limiting examples of methods that can be used to generate probes include nick translation, random oligo primed synthesis, and end labeling.

A variety of assays for determining the genotype of a gene are known in the art. Non-limiting examples of such assays (which can be used in any of the methods described herein) include: dynamic allele-specific hybridization (see, e.g., Howell et al., Nature Biotechnol. 17:87-88, 1999), molecular beacon assays (see, e.g., Marras et al., “Genotyping Single Nucleotide Polymorphisms with Molecular Beacons,” In Kwok (Ed.), Single Nucleotide Polymorphisms: Methods and Protocols, Humana Press, Inc., Totowa, NJ, Vol. 212, pp. 111-128, 2003), microarrays (see, e.g., Affymetrix Human SNP 5.0 GeneChip), restriction fragment length polymorphism (RFLP) (see, e.g., Ota et al., Nature Protocols 2:2857-2864, 2007), PCR-based assays (e.g., tetraprimer ARMS-PCR (see, e.g., Zhang et al., Pios One 8:e62126, 2013), real-time PCR, allele-specific PCR (see, e.g., Gaudet et al., Methods Mol. Biol. 578:415-424, 2009), and TaqMan Assay SNP Genotyping (see, e.g., Woodward, Methods Mol. Biol. 1145:67-74, 2014, and TaqMan®Open Array® Genotyping Plates from Life Technologies)), Flap endonuclease assays (also called Invader assays) (see, e.g., Olivier et al., Mutat. Res. 573 : 103-110, 2005), oligonucleotide ligation assays (see, e.g., Bruse et al., Biotechniques 45:559-571, 2008), single strand conformational polymorphism assays (see, e.g., Tahira et al., Human Mutat. 26:69-77, 2005), temperature gradient gel electrophoresis (see, e.g., Jones et al., “Temporal Temperature Gradient Electrophoresis for Detection of Single Nucleotide Polymorphisms,” in Single Nucleotide Polymophisms: Methods and Protocols, Volume 578, pp. 153-165, 2008) or temperature gradient capillary electrophoresis, denaturing high performance liquid chromatography (see, e.g., Yu et al., J. Clin. Pathol. 58:479-485, 2005), high-resolution melting of an amplified sequence containing the SNP (see, e.g., Wittwer et al., Clinical Chemistry 49:853-860, 2003), or sequencing (e.g., Maxam-Gilbert sequencing, chain-termination methods, shotgun sequencing, bridge PCR, and nextgeneration sequencing methods (e.g., massively parallel signature sequencing, polony sequencing, 454 pyrosequencing, Illumina (Solexa) sequencing, SOLiD sequencing, Ion Torrent semiconductor sequence, DNA nanoball sequencing, heliscope single molecule sequencing, and single molecule real-time sequencing). Additional details and a summary of various next-generation sequencing methods are described in Koboldt et al., Cell 155:27-38, 2013.

In some embodiments of any of the methods described herein, the genotyping of a gene includes a PCR assay (e.g., a real-time PCR-assay) (with or without a prior preamplification step (e.g., any of the pre-amplification methods described herein)). In some embodiments of any of the methods described herein the genotyping can be performed using TaqMan®-based sequencing (e.g., TaqMan®-based OpenArray® sequencing, e.g., high throughput TaqMan®-based Open Array® sequencing) (with or without a prior preamplification step (e.g., any of the pre-amplification methods described herein)).

In some embodiments of any of the methods described herein, the level of the protein or mRNA can be detected in a biological sample including blood, serum, exosomes, plasma, tissue, urine, feces, sputum, and cerebrospinal fluid.

In some embodiments of any of the methods described herein, the level of at least one (e.g., 2, 3, 4, 5, 6, 7 or 8) parameters related to cGAS/STING signaling pathway activity and/or expression can be determined, e.g., in any combination.

In one aspect, the cell can be a cell isolated from a subject who has been screened for the presence of a cancer or an indication that is associated with an increase in a cGAS/STING signaling pathway activity and/or a decrease in ATM level or activity.

Reference Levels

In some embodiments of any of the methods described herein, the reference level can be a corresponding level detected in a similar cell or sample obtained from a healthy subject (e.g., a subject that has not been diagnosed or identified as having a cancer, or any disorder associated with increased cGAS/STING signaling pathway activity and/or decreased ATM level and/or activity) (e.g., a subject who is not suspected or is not at increased risk of developing a cancer, or any disorder associated with increased cGAS/STING signaling pathway and/or decreased ATM level and/or activity activity and/or expression) (e.g., a subject that does not present with any symptom of a cancer, or any disorder associated with increased cGAS/STING signaling pathway activity and/or decreased ATM level and/or activity).

In some embodiments, a reference level can be a percentile value (e.g., mean value, 99% percentile, 95% percentile, 90% percentile, 85% percentile, 80% percentile, 75% percentile, 70% percentile, 65% percentile, 60% percentile, 55% percentile, or 50% percentile) of the corresponding levels detected in similar samples in a population of healthy subjects (e.g., a population of subjects that have not been diagnosed or identified as having a cancer, or any disorder associated with increased cGAS/STING signaling pathway and/or decreased ATM level and/or activity) (e.g., a population of subjects who are not suspected or are not at increased risk of developing a cancer, or any disorder associated with increased cGAS/STING signaling pathway and/or decreased ATM level and/or activity) (e.g., a population of subjects that do not present with any symptom of a cancer, or any disorder associated with increased cGAS/STING signaling pathway and/or decreased ATM level and/or activity).

In some embodiments, a reference can be a corresponding level detected in a similar sample obtained from the subject at an earlier time point.

STING Antagonists

In any of the methods described herein, the STING antagonist can be any of the

STING antagonists described herein (e.g., any of the compounds described in this section). In any of the methods described herein, the STING antagonist has an IC50 of between about 1 nM and about 10 pM for STING.

In some embodiments, the STING antagonist is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, wherein:

Z, Y ¹ , Y ² , Y ³ , Y ⁴ , X ¹ , X ² , W, Q, and A can be as defined anywhere in WO 2020/010092, filed as PCT/US2019/040317 on July 2, 2019; US Provisional 62/693,768, filed on July 3, 2018; and US Provisional 62/861,825, filed on June 14, 2019, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , Y ⁴ , X ¹ , X ² , W, Q, and A are as defined in any one of claims 1 to 255 in WO 2020/010092, filed as PCT/US2019/040317 on July 2, 2019, each of which is incorporated herein by reference in its entirety. In certain embodiments, the STING antagonist is a compound as described in the table spanning pages 93 to 158 in WO 2020/010092, filed as PCT/US2019/040317 on July 2, 2019, which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:

Y ¹ , Y ² , X, Z, W, Q, and A can be as defined anywhere in WO 2020/010155, filed as PCT/US2019/040418 on July 2, 2019; US Provisional 62/693,878, filed on July 3, 2018; and US Provisional 62/861,078, filed on June 13, 2019, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Y ¹ , Y ² , X, Z, W, Q, and A are as defined in any one of claims 1 to 115 in WO 2020/010155, filed as PCT/US2019/040418 on July 2, 2019, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in the table spanning pages 34 to 44 in WO 2020/010155, filed as PCT/US2019/040418 on July 2, 2019, which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (III): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:

A, W ¹ , W ² , and B can be as defined anywhere in WO 2020/150417, filed as PCT/US2020/013786 on January 16, 2020; U.S. Provisional 62/793,795, filed on January 17, 2019; U.S. Provisional 62/861,865, filed on June 14, 2019; U.S. Provisional 62/869,914, filed on July 2, 2019; and U.S. Provisional 62/955,891, filed on December 31, 2019, each of which is incorporated herein by reference in its entirety. In certain of these embodiments, A, W ¹ , W ² , and B are as defined in any one of claims 1 to 116 in WO 2020/150417, filed as PCT/US2020/013786 on January 16, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:

Z, Y ¹ , Y ² , Y ³ , R ⁶ , B, R ^2N , L ³ , and R ⁴ can be as defined anywhere in WO

2020/150417, filed as PCT/US2020/013786 on January 16, 2020; U.S. Provisional 62/793,795, filed on January 17, 2019; U.S. Provisional 62/861,865, filed on June 14, 2019; U.S. Provisional 62/869,914, filed on July 2, 2019; and U.S. Provisional 62/955,891, filed on December 31, 2019, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , R ⁶ , B, R ^2N , L ³ , and R ⁴ are as defined in any one of claims 117 to 223 in WO 2020/150417, filed as PCT/US2020/013786 on January 16, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of WO 2020/150417, filed as PCT/US2020/013786 on January 16, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (V): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein: X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z, Q, A, and R ⁶ can be as defined anywhere in WO 2020/236586, filed as PCT/US2020/033127 on May 15, 2020; U.S. Provisional 62/849,811, filed on May 17, 2019; and U.S. Provisional 62/861,880, filed on June 14, 2019; each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z, Q, A, and R ⁶ are as defined in any one of claims 1 to 18 and any one of the numbered clauses 1 to 271 in WO 2020/236586, filed as PCT/US2020/033127 on May 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of WO 2020/236586, filed as PCT/US2020/033127 on May 15, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (VI): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:

X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z, W, and R ⁶ can be as defined anywhere in WO 2020/243519 filed as PCT/US2020/035249 on May 29, 2020; U.S. Provisional 62/854,288, filed on May 29, 2019, which is incorporated herein by reference in its entirety.

In certain of these embodiments, X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z, W, and R ⁶ are as defined in any one of claims 1 to 16 and any one of numbered clauses 1-223 and 279-287 in WO 2020/243519 filed as PCT/US2020/035249 on May 29, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in the Table Cl of WO 2020/243519 filed as PCT/US2020/035249 on May 29, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (VII): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:

Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , R ⁶ , W, and A can be as defined anywhere in WO 2020/252240 filed as PCT/US2020/037403 on June 12, 2020; U.S. Provisional 62/861,714, filed on June 14, 2019; and U.S. Provisional 62/955,924, filed on December 31, 2019; each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , R ⁶ , W, and A are as defined in any one of claims 1 to 16 and any one of numbered clauses 1 to 328 in PCT/US2020/037403 filed on June 12, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2020/037403 filed on June 12, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Q, and A can be as defined anywhere in WO 2020/106741 filed as PCT/US2019/062245 on November 19, 2019; U.S. Provisional 62/769,500, filed on November 19, 2018; and U.S. Provisional 62/861,108, filed on June 13, 2019; each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , W, Q, and A are as defined in any one of claims 1 to 118 in WO 2020/106741 filed as PCT/US2019/062245 on November 19, 2019, each of which is incorporated herein by reference in its entirety. In certain embodiments, the STING antagonist is a compound as described in table spanning pages 56-69 in WO 2020/106741 filed as PCT/US2019/062245 on November 19, 2019, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (IX): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:

A, B, W, and R ^N can be as defined anywhere in WO 2020/106736 filed as PCT/US2019/062238 on November 19, 2019; U.S. Provisional 62/769,327, filed on November 19, 2018 and U.S. Provisional 62/861,781, filed on June 14, 2019, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, A, B, W, and R ^N are as defined in any one of claims 1 to 298 in WO 2020/106736 filed as PCT/US2019/062238 on November 19, 2019, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table 1A and Table IB of WO 2020/106736 filed as PCT/US2019/062238 on November 19, 2019, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (X): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein:

A, B, and L ^AB can be as defined anywhere in WO 2020/150439 filed as PCT/US2020/013824 on January 16, 2020; U.S. Provisional 62/793,623, filed on January 17, 2019; and U.S. Provisional 62/861,702, filed on June 14, 2019; each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, A, B, and L ^AB are as defined in any one of claims 1 to 116 and 172-249 in WO 2020/150439 filed as PCT/US2020/013824 on January 16, 2020, each of which is incorporated herein by reference in its entirety. In certain embodiments, the STING antagonist is a compound as described in Table Cl of WO 2020/150439 filed as PCT/US2020/013824 on January 16, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XI): or a pharmaceutically acceptable salt thereof, or a tautomer therefore, wherein:

X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z, Q, A, and R ⁶ can be as defined anywhere in WO 2021/067791, filed as PCT/US2020/054054 on October 2, 2020; U.S. Provisional 62/910,162, filed on October 3, 2019; and U.S. Provisional 62/955,921, filed on December 31, 2019; each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, X ¹ , X ² , Y ¹ , Y ² , Y ³ , Y ⁴ , Z, Q, A, and R ⁶ are as defined in any one of claims 1 to 16 and any one of the numbered clauses 1 to 179 in PCT/US2020/054054 filed on October 2, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2020/054054 filed on October 2, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XII): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein: R ^la , R ^lb , R ^lc , R ^ld , X ¹ , X ² , Q, A, and R ⁶ can be as defined anywhere in WO 2021/067805 filed as PCT/US2020/054069 filed on October 2, 2020; U.S. Provisional 62/910,160, filed on October 3, 2019; and U.S. Provisional 62/955,867, filed on December 31, 2019; each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, R ^la , R ^lb , R ^lc , R ^ld , X ¹ , X ² , Q, A, and R ⁶ are as defined in any one of claims 1 to 16 and any one of the numbered clauses 1 to 296 in PCT/US2020/054069 filed on October 2, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of in PCT/US2020/054069 filed on October 2, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XIII): or a pharmaceutically acceptable salt, or a tautomer thereof, wherein:

R ^la , R ^lb , R ^lc , R ^ld , X ¹ , X ² , W, Q, A, and R ⁶ can be as defined anywhere in WO 2021/067801 filed as PCT/US2020/054064 on October 2, 2020; U.S. Provisional 62/910,230, filed on October 3, 2019; and U.S. Provisional 62/955,899, filed on December 31, 2019; each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, R ^la , R ^lb , R ^lc , R ^ld , X ¹ , X ² , W, Q, A, and R ⁶ are as defined in any one of claims 1 to 16 and any one of the numbered clauses 1 to 181 in PCT/US2020/054064 filed on October 2, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2020/054064 filed on October 2, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XIV): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , W, Q, P ¹ , P ² , P ³ , P ⁴ , and P ⁵ can be as defined anywhere in WO 2021/138419 filed as PCT/US2020/067463 on December 30, 2020; U.S. Provisional 63/090,547 filed on October 12, 2020; and U.S. Provisional 62/955,853 filed on December 31, 2019, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , W, Q, P ¹ , P ² , P ³ , P ⁴ , and P ⁵ are as defined in any one of claims 1 to 16 and any one of the numbered clauses 1 to 220 in U.S. Provisional 63/090,547 filed on October 12, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of U.S. Provisional Application Serial No. 63/090,547 filed on October 12, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XV): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

R ^la , R ^lb , R ^lc , R ^ld , X ¹ , X ² , R ⁶ , W, Q, P ¹ , P ² , P ³ , P ⁴ , and P ⁵ can be as defined anywhere in WO 2021/138434 filed as PCT/US2020/067483 on December 30, 2020; U.S. Provisional 63/090,538 filed on October 12, 2020; and U.S. Provisional 62/955,839 filed on December 31, 2019, each of which is incorporated herein by reference in its entirety. In certain of these embodiments, R ^la , R ^lb , R ^lc , R ^ld , X ¹ , X ² , R ⁶ , W, Q, P ¹ , P ² , P ³ , P ⁴ , and P ⁵ are as defined in any one of claims 1 to 16 and any one of the numbered clauses 1 to 240 in U.S. Provisional 63/090,538 filed on October 12, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of U.S. Provisional 63/090,538 filed on October 12, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XVI): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

Q ² , L ^A , al, Ring Q ¹ , Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ and W can be defined anywhere in PCT/US2021/041823, filed on July 15, 2021; and U.S. Provisional 63/052,084 filed on July 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Q ² , L ^A , al, Ring Q ¹ , Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ and W are as defined in any one of claims 1 to 20 and any one of the numbered clauses 1 to 176 in PCT/US2021/041823 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2021/041823 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XVII): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , P ¹ , P ² , P ³ , P ⁴ , and P ⁵ can be defined anywhere in PCT/US2021/041820, filed on July 15, 2021; and U.S. Provisional 63/052,086 filed on July 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , P ¹ , P ² , P ³ , P ⁴ , and P ⁵ are as defined in any one of claims 1 to 19 and any one of the numbered clauses 1 to 193 in PCT/US2021/041820 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2021/041820 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XVIII): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^A , al, and Ring C can be defined anywhere in PCT/US2021/041817, filed on July 15, 2021; and U.S. Provisional 63/052,080 filed on July 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^A , al, and Ring C are as defined in any one of claims 1 to 20 and any one of the numbered clauses 1 to 196 in PCT/US2021/041817 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2021/041817 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XIX): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^A , al, Ring C and R ⁷ can be defined anywhere in PCT/US2021/041792, filed on July 15, 2021; and U.S. Provisional 63/052,117 filed on July 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^A , al, Ring C and R ⁷ are as defined in any one of claims 1 to 17 and any one of the numbered clauses 1 to 173 in PCT/US2021/041792, filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2021/041792 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XX): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

Q ² , L ^A , al, Q ¹ , Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ and W can be defined anywhere in U.S. utility application 17/376,823, filed on July 15, 2021; and U.S. Provisional 63/052,076, filed on July 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Q ² , L ^A , al, Q ¹ , Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ and W and Ring C are as defined in any one of claims 1 to 19 and any one of the numbered clauses 1 to 186 in U.S. utility application 17/376,823 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety. In certain embodiments, the STING antagonist is a compound as described in Table Cl of U.S. utility application 17/376,823 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XXI): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^B , L ^A , al, and Ring C can be defined anywhere in U.S. utility application 17/376,829, filed on July 15, 2021; and U.S. Provisional 63/052,052, filed on July 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , Ring B, L ^B , L ^A , al, and Ring C are as defined in any one of claims 1 to 17 and any one of the numbered clauses 1 to 181 in U.S. utility application 17/376,829 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of U.S. utility application 17/376,829 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XXII): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , and Ring B can be defined anywhere in PCT/US2021/041758, filed on July 15, 2021; and U.S. Provisional 63/052,083 filed on July 15, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, Z, Y ¹ , Y ² , Y ³ , X ¹ , X ² , R ⁶ , and Ring B are as defined in any one of claims 1 to 18 and any one of the numbered clauses 1 to 157 in PCT/US2021/041758 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of PCT/US2021/041758 filed on July 15, 2021, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XXIII): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

X ¹ , X ² , X ³ , Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ , R ⁶ , and m can be defined anywhere in U.S. Provisional 63/126,332 filed on December 16, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, X ¹ , X ² , X ³ , Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ , R ⁶ , and m are as defined in any one of claims 1 to 20 and any one of the numbered clauses 1 to 174 in U.S. Provisional 63/126,332 filed on December 16, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of U.S. Provisional 63/126,332 filed on December 16, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (XXIV): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein

X ¹ , X ² , X ³ , Y ¹ , Y ² , Y ³ , R ³ , and Ring A can be defined anywhere in U.S. Provisional 63/126,286 filed on December 16, 2020, each of which is incorporated herein by reference in its entirety.

In certain of these embodiments, X ¹ , X ² , X ³ , Y ¹ , Y ² , Y ³ , R ³ , and Ring A are as defined in any one of claims 1 to 23 and any one of the numbered clauses 1 to 183 in U.S. Provisional 63/126,286 filed on December 16, 2020, each of which is incorporated herein by reference in its entirety.

In certain embodiments, the STING antagonist is a compound as described in Table Cl of U.S. Provisional 63/126,286 filed on December 16, 2020, each of which is incorporated herein by reference in its entirety.

In some embodiments, the STING antagonist is a compound of Formula (Ml): or a pharmaceutically acceptable salt thereof, wherein:

Ring B is selected from the group consisting of: (B-l), (B-2), and (B-3);

(B-3);

X ¹ is selected from the group consisting of O, S, N, NR ² , and CR ⁵ ; X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each of Z, Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of: CR ¹ , N, and NR ² ;

Y ⁴ is C or N; each — is independently a single bond or a double bond;

• provided that in (B-l), (B-2), and (B-3), the five-membered ring comprising X ¹ and X ² is heteroaryl; provided that in (B-l), the 6-membered ring is aromatic; provided that in (B-2), the 6-membered ring is aromatic, and one or more of Z, Y ¹ , Y ² , Y ³ , and Y ⁴ in (B-2) is an independently selected heteroatom; and provided that in (B-3), the 6-membered ring is aromatic;

W is selected from the group consisting of:

*C(=O)NR ^N , *C(=S)NR ^N , *C(=NR ^N )NR ^N , *C(=NCN)NR ^N ,

*C(=CNO ₂ )NR ^N *S(O)I- ₂ NR ^N ;

*C(=O), *S(O) ₂ ; • , wherein Q ² is selected from the group consisting of: a bond, NR ^N , -S-, and -O-; each R ^N is independently selected from the group consisting of: H and R ^d , and the asterisk represents point of attachment to NR ⁶ ;

A is:

(i) -(Y ^A1 ) _n -Y ^A2 , wherein:

• n is 0 or 1;

• Y ^A1 is Ci-6 alkylene, which is optionally substituted with 1-6 R ^a ;

• Y ^A2 is:

(a) C3-20 cycloalkyl or C3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R ^b ,

(b) C6-20 aryl which is optionally substituted with 1-4 R ^c ;

(c) heteroaryl of 5-20 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected R ^c ; or

(d) heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R ^b , or

(ii) Ci -20 alkyl, which is optionally substituted with 1-6 independently selected R ^a ; each of R ¹ , R ^la , R ^lb , R ^lc , and R ^ld is independently selected from the group consisting of: H; halo; cyano; C1-6 alkyl optionally substituted with 1-2 R ^a ; C2-6 alkenyl; C2-6 alkynyl; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -L ³ -L ⁴ -R‘; -S(O)i-2(Ci-4 alkyl); -S(O)(=NH)(CI-4 alkyl); SF ₅ ; -NR ^e R ^f ; -OH; oxo; -S(O)I- ₂ (NR’R”); -Ci-4 thioalkoxy; - NO ₂ ; -C(=O)(Ci- ₄ alkyl); -C(=O)O(Ci- ₄ alkyl); -C(=O)OH; and -C(=O)N(R’)(R”); each occurrence of R ² is independently selected from the group consisting of:

(i) C _1-6 alkyl, which is optionally substituted with 1-2 independently selected R ^a ;

(ii) C _3-6 cycloalkyl, C3-6 cycloalkenyl, or C _6-10 aryl;

(iii) heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2;

(iv) heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2;

(v) -C(O)(C _1-4 alkyl); -C(O)O(C _1-4 alkyl); -CON(R’)(R”); -S(O) _1-2 (NR’R”); - S(O) _1-2 (C _1-4 alkyl); -OH; C _1-4 alkoxy; and

(vi) H;

R ⁴ is selected from the group consisting of H and C1-6 alkyl optionally substituted with 1-3 independently selected R ^a ;

R ⁵ is selected from the group consisting of H; halo; -OH; -C _1-4 alkyl; -C _1-4 haloalkyl; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1-4 alkyl); - C(=O)OH; -CON(R’)(R”); -S(O) _1-2 (NR’R”); -S(O) _1-2 (C _1-4 alkyl); cyano; and C _3-6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected _C1-4 alkyl;

R ⁶ is selected from the group consisting of H; C _1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -OH; C _1-4 alkoxy; C(=O)H; C(=O)(C _1-4 alkyl); C _6-10 aryl optionally substituted with 1-4 independently selected C _1-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0) _0-2 and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C _1-4 alkyl; each occurrence of R ^a is independently selected from the group consisting of: - OH; -F; -Cl; -Br; -NR ^e R ^f ; C _1-4 alkoxy; C _1-4 haloalkoxy; -C(=O)O(C _1-4 alkyl); -C(=O)(C _1- 4 alkyl); -C(=O)OH; -CON(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (C _1-4 alkyl); cyano, and C3- 6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected Ci-4 alkyl; each occurrence of R ^b is independently selected from the group consisting of: Ci- 10 alkyl optionally substituted with 1-6 independently selected R ^a ; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR ^e R ^f ; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-io alkyl); -C(=O)O(Ci- 4 alkyl); -C(=O)OH; -C(=O)N(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci- ₄ alkyl); and cyano; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C ₂ -6 alkenyl; C ₂ -6 alkynyl; oxo; Ci-4 alkoxy optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkoxy; -S(O)i- ₂ (Ci-4 alkyl) or -S(O)i- ₂ (Ci-4 haloalkyl); -NR ^e R ^f ; - OH; -S(O)I- ₂ (NR’R”); -CI-4 thioalkoxy or -Ci-4 thiohaloalkoxy; -NO ₂ ; -SF5; -C(=O)(Ci- 10 alkyl); -C(=O)O(Ci- ₄ alkyl); -C(=O)OH; -C(=O)N(R’)(R”); and -XAlAR ¹¹ ;

R ^d is selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C3-6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; -C(O)(Ci-4 alkyl); - C(O)O(Ci-4 alkyl); -CON(R’)(R”); -S(O)I- ₂ (NR’R”); - S(O)i- ₂ (Ci- ₄ alkyl); -OH; and Ci-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C1-6 alkyl; C1-6 haloalkyl; C3-6 cycloalkyl or C3-6 cycloalkenyl; -C(O)(Ci-4 alkyl); - C(O)O(Ci-4 alkyl); -CON(R’)(R”); -S(O)I- ₂ (NR’R”); - S(O)i- ₂ (Ci- ₄ alkyl); -OH; and Ci-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R ^e and R ¹ ), which are each independently selected from the group consisting of N(R ^d ), NH, O, and S;

-L ¹ is a bond or C1-3 alkylene;

-L ² is -O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o- ₂ -, or a bond;

-L ³ is a bond or C1-3 alkylene; -L ⁴ is — O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o-2-, or a bond; each occurrence of R ^h and R‘ is independently selected from the group consisting of:

• C3-8 cycloalkyl or C3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy; and

• Ce-io aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, Ce-io aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, -OH, NH ₂ , NH(CI-4 alkyl), N(CI-4 alkyl) ₂ , Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(CI-6 alkyl), O, and S.

In certain embodiments of Formula (Ml), Ring B is (B-2) (e.g„ such as ); and W is selected from the group consisting of: *C(=O)NR ^N ,

*C(=S)NR ^N , *C(=NR ^N )NR ^N , *C(=NCN)NR ^N , *C(=CNO ₂ )NR ^N *S(O)I- ₂ NR ^N ; (e.g., C(=O)NR ^N , such as C(=O)NH).

In certain embodiments of Formula (Ml), Ring B is (B-l) (e.g., In certain embodiments of Formula (Ml), Ring B is (B-l) (e.g.,

In certain embodiments of Formula (Ml), Ring B is (B-3) (e.g., ); and W is C(=O)NR ^N (e.g., C(=O)NH). certain embodiments of Formula (Ml), Ring B is (B-l) (e.g., , ); W is C(=O)NR ^N (e.g., C(=O)NH); and one of R ^la , R ^lb , R ^lc , and R ^ld (e.g., R ^lb ) is -lAV-R^e.g., -R‘). In some embodiments, the STING antagonist is a compound of Formula (M2):

Formula (M2) or a pharmaceutically acceptable salt thereof, wherein:

W is defined according to (AA) or (BB) below:

(AA)

W is Qi-Q ² -A, wherein

Q ¹ is selected from the group consisting of:

(a) phenyl optionally substituted with from 1-2 independently selected R ^ql ; and

(b) heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R ^ql ;

Q ² is selected from the group consisting of: a bond, -NH-, -N(CI-3 alkyl)-, -O-, - C(=O), and -S(0)o-2-;

A is as defined for Formula (Ml) herein; or

(BB)

W is selected from the group consisting of:

(a) C7-20 bicyclic or polycyclic aryl, which is optionally substituted with from 1-4 R ^c ; and

(b) bicyclic or polycyclic heteroaryl including from 7-20 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with from 1-4 independently selected R ^c ; each occurrence of R ^ql is independently selected from the group consisting of:

(a) halo; (b) cyano; (c) C1-10 alkyl which is optionally substituted with from 1-6 independently selected R ^a ; (d) C2-6 alkenyl; (e) C2-6 alkynyl; (f) C3-6 cycloalkyl; (g) Ci-4 alkoxy; (h) Ci-4 haloalkoxy; (i) -S(O)i- ₂ (Ci-4 alkyl); (j) -NR ^e R ^f ; (k) -OH; (1) -S(O)i- ₂ (NR’R”); (m) -Ci-4 thioalkoxy; (n) -NO ₂ ; (o) -C(=O)(Ci- ₄ alkyl); (p) -C(=O)O(Ci- ₄ alkyl); (q) -C(=O)OH; (r) -C(=O)N(R’)(R”); and (s) oxo; and

Ring B, R ⁶ , R ^a , R ^c , R ^d , R ^e , R ^f , R’, and R” are each as defined for Formula (Ml) herein.

In certain embodiments of Formula (M2), Ring B is (B-3) (e.g.,

In some embodiments, the STING antagonist is a compound of Formula (M3): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

X ¹ is selected from the group consisting of O, S, N, NR ² , and CR ⁵ ; X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that the fivemembered ring comprising X ¹ and X ² is heteroaryl; and the 6-membered ring is aromatic;

Q-A is defined according to (A) or (B) below:

(A)

Q is selected from the group consisting of: NH and N(CI-6 alkyl) wherein the Ci-6 alkyl is optionally substituted with 1-2 independently selected R ^a ; and

A is:

(i) -(Y ^A1 ) _n -Y ^A2 , wherein:

• n is 0 or 1;

• Y ^A1 is Ci-6 alkylene, which is optionally substituted with 1-6 substituents each independently selected from the group consisting of: o oxo; o R ^a ; o Ce-io aryl optionally substituted with 1-4 independently selected Ci- 4 alkyl; and o heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Ci-4 alkyl; or

• Y ^A1 is -Y ^A3 -Y ^A4 -Y ^A5 which is connected to Q via Y ^A3 wherein: o Y ^A3 is a Ci-3 alkylene optionally substituted with 1-2 substituents each independently selected from the group consisting of oxo and R ^a ; o Y ^A4 is -O-, -NH-, -N(CI-6 alkyl)-, or -S-; and o Y ^A5 is a bond or C1-3 alkylene which is optionally substituted with 1-2 independently selected R ^a ; and

• Y ^A2 is:

(a) C3-20 cycloalkyl or C3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R ^b ,

(b) C6-20 aryl which is optionally substituted with 1-4 R ^c ;

(c) heteroaryl of 5-20 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected R ^c ; or

(d) heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R ^b , or

(ii) -Z ³ -Z ² -Z ³ , wherein:

• Z ¹ is C1-3 alkylene, which is optionally substituted with 1-4 R ^a ;

• Z ² is -N(H)-, -N(R ^d )-, -O-, or -S-; and

• Z ³ is C2-7 alkyl, which is optionally substituted with 1-4 R ^a ; or

(iii) Ci -20 alkyl, which is optionally substituted with 1-6 independently selected R ^a , or

Q and A, taken together, form: and

E is a ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in additionitrogen atom this is already present), each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein the ring is optionally substituted with 1-4 independently selected R ^b , each of R ^la , R ^lb , R ^lc , and R ^ld is independently selected from the group consisting of: H; halo; cyano; Ci-6 alkyl optionally substituted with 1-2 R ^a ; C2-6 alkenyl; C2-6 alkynyl; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -L ³ -L ⁴ -R‘; -S(O)i-2(Ci-4 alkyl); - S(O)(=NH)(C 1-4 alkyl); SF ₅ ; -NR ^e R ^f ; -OH; oxo; -S(O)I- ₂ (NR’R”); -Ci-4 thioalkoxy; -NO2; -C(=O)(Ci-4 alkyl); -C(=O)O(Ci- ₄ alkyl); -C(=O)OH; and -C(=O)N(R’)(R”); or

R ^la and R ^lb , R ^lb and R ^lc , or R ^lc and R ^ld , taken together with the atoms connecting them, form a ring of 3-10 ring atoms, wherein 0-2 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2; and wherein the ring is optionally substituted with 1-4 substituents each independently selected from the group consisting of C1-6 alkyl, halo, C1-6 haloalkyl, -OH, NR ^e R ^f , C1-6 alkoxy, and C1-6 haloalkoxy, each occurrence of R ² is independently selected from the group consisting of:

(i) C1-6 alkyl, which is optionally substituted with 1-2 independently selected R ^a ;

(ii) C3-6 cycloalkyl, C3-6 cycloalkenyl, or Ce-io aryl;

(iii) heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2;

(iv) heteroaryl of 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2;

(v) -C(O)(Ci- ₄ alkyl); -C(O)O(Ci- ₄ alkyl); -CON(R’)(R”); -S(O)I- ₂ (NR’R”); - S(O)i-2(Ci-4 alkyl); -OH; Ci-4 alkoxy; and

(vi) H;

R ⁴ is selected from the group consisting of H and C1-6 alkyl optionally substituted with 1-3 independently selected R ^a ;

R ⁵ is selected from the group consisting of H; halo; -OH; -Ci-4 alkyl; -Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); - C(=O)OH; -CON(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci-4 alkyl); cyano; and C3-6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected Ci-4 alkyl;

R ⁶ is selected from the group consisting of H; C1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -OH; Ci-4 alkoxy; C(=O)H; C(=O)(Ci-4 alkyl); Ce-io aryl optionally substituted with 1-4 independently selected Ci-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Ci-4 alkyl; each occurrence of R ^a is independently selected from the group consisting of: - OH; -F; -Cl; -Br; -NR ^e R ^f ; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci- 4 alkyl); -C(=O)OH; -CON(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci- ₄ alkyl); cyano, and C3- 6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected Ci-4 alkyl; each occurrence of R ^b is independently selected from the group consisting of: Ci- 10 alkyl optionally substituted with 1-6 independently selected R ^a ; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR ^e R ^f ; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-io alkyl); -C(=O)O(Ci- 4 alkyl); -C(=O)OH; -C(=O)N(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci- ₄ alkyl); cyano; and -L ¹ -L ² -R ^h ; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C ₂ -6 alkenyl; C ₂ -6 alkynyl; oxo; Ci-4 alkoxy optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkoxy; -S(O)i- ₂ (Ci-4 alkyl) or -S(O)i- ₂ (Ci-4 haloalkyl); -NR ^e R ^f ; - OH; -S(O)I- ₂ (NR’R”); -CI-4 thioalkoxy or -C 1-4 thiohaloalkoxy; -NO ₂ ; -SF5; -C(=O)(Ci- 10 alkyl); -C(=O)O(Ci-4 alkyl); -C(=O)OH; -C(=O)N(R’)(R”); and -XAIAR ¹¹ ;

R ^d is selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C3-6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; -C(O)(Ci-4 alkyl); - C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(O)I- ₂ (NR’R”); - S(O)i- ₂ (Ci- ₄ alkyl); -OH; and Ci-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; Ci-6 alkyl; Ci-6 haloalkyl; C3-6 cycloalkyl or C3-6 cycloalkenyl; -C(O)(Ci-4 alkyl); - C(O)O(Ci- ₄ alkyl); -CON(R’)(R”); -S(O)I- ₂ (NR’R”); - S(O)i- ₂ (Ci-4 alkyl); -OH; and Ci-4 alkoxy; or R ^e and R ^f together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R ^e and R ¹ ), which are each independently selected from the group consisting of N(R ^d ), NH, O, and S;

-L ¹ is a bond or C1-3 alkylene;

-L ² is -O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o- ₂ -, or a bond;

R ^h is selected from the group consisting of:

• C3-8 cycloalkyl or C3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ , wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o- ₂ and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy; and • Ce-io aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy;

-L ³ is a bond or C1-3 alkylene;

-L ⁴ is -O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o-2-, or a bond;

R‘ is selected from the group consisting of:

• C3-8 cycloalkyl or C3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy; and

• Ce-io aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy; and each occurrence of R’ and R” is independently selected from the group consisting of: H, Ci-4 alkyl, Ce-io aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, -OH, NH2, NH(CI-4 alkyl), N(CI-4 alkyl)2, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(CI-6 alkyl), O, and S.

In certain embodiments of Formula (M3), the compound is a compound of Formula (M3 A): or a pharmaceutically acceptable salt thereof, wherein: ml and m2 are independently 0, 1, or 2;

Q ⁵ is N or CH;

L ⁵ is a bond, CH2, -O-, -N(H)-, or -N(CI-3 alkyl), provided that when Q ⁵ is N, then L ⁵ is a bond or CH2;

T ¹ , T ² , T ³ , and T ⁴ are each independently N, CH, or CR‘, provided that 1-4, such as 2, 3, or 4, of T ⁴ -T ⁴ is CH; and each of R‘ and R ^s is independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci- 4 alkoxy; and Ci-4 haloalkoxy, optionally wherein R ² is H, and R ⁵ is H; and optionally wherein R ^lb is halo, such as -F or -Cl; R ^lc is H or halo, such as -H or -

F; and R ^la and R ^ld are H.

In some embodiments, the STING antagonist is a compound of Formula (M4): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:

Z is selected from the group consisting of CR ¹ , N, and NR ² ; each of Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of CR ¹ , N, and NR ² ;

Y ⁴ is C or N, provided that one or more of Z, Y ¹ , Y ² , Y ³ , and Y ⁴ is an independently selected heteroatom;

X ¹ is selected from the group consisting of O, S, N, NR ² , and CR ¹ ;

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that the fivemembered ring comprising Y ⁴ , X ¹ , and X ² is heteroaryl, and the 6-membered ring comprising Z, Y ¹ , Y ² , and Y ³ is heteroaryl; each occurrence of R ¹ is independently selected from the group consisting of:

H; halo; cyano; Ci-6 alkyl optionally substituted with 1-2 R ^a ; C2-6 alkenyl; C2-6 alkynyl; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -L ³ -L ⁴ -R‘; -S(O)i-2(Ci-4 alkyl); - S(O)(=NH)(C 1-4 alkyl); SF ₅ ; -NR ^e R ^f ; -OH; oxo; -S(O)I- ₂ (NR’R”); -Ci-4 thioalkoxy; -NO2; -C(=O)(Ci-4 alkyl); -C(=O)O(Ci- ₄ alkyl); -C(=O)OH; and -C(=O)N(R’)(R”); each of R ² , R ⁴ , R ⁵ , R ⁶ , Q, A, R ^a , R ^e , R ^f , L ³ , L ⁴ , R‘, R’, and R” are as defined for Formula M3 herein.

In some embodiments, the STING antagonist is a compound of Formula (M5): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: X ¹ is selected from the group consisting of O, S, N, NR ² , and CR ¹ ;

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that: the five-membered ring comprising X ¹ and X ² is heteroaryl; the 6-membered ring and the ring comprising P ¹ , P ² , P ³ , P ⁴ , and P ⁵ is aromatic;

P ¹ , P ² , P ³ , P ⁴ , and P ⁵ are defined according to (AA) or (BB):

(AA) each of P ¹ , P ² , P ³ , P ⁴ , and P ⁵ is independently selected from the group consisting of: N, CH, CR ⁷ , and CR ^C , provided that 1-2 of P ¹ , P ² , P ³ , P ⁴ , and P ⁵ is an independently selected CR ⁷ ; or

(BB)

P ¹ is absent, thereby providing a 5-membered ring, each of P ² , P ³ , P ⁴ , and P ⁵ is independently selected from the group consisting of O, S, N, NH, NR ^d , NR ⁷ , CH, CR ⁷ , and CR ^C , provided that 1-3 of P ² , P ³ , P ⁴ , and P ⁵ is O, S, N, NH, NR ^d , or NR ⁷ ; and 1-2 of P ² , P ³ , P ⁴ , and P ⁵ is an independently selected NR ⁷ or CR ⁷ ; each R ⁷ is independently selected from the group consisting of: -R ⁸ and -L ³ -R ⁹ ;

R ⁸ and R ⁹ are independently selected from the group consisting of:

(a) C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 independently selected R ⁷ ’;

(b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R ⁷ ’;

(c) heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with 1-4 independently selected R ⁷ ’; and

(d) Ce-io aryl optionally substituted with 1-4 independently selected R ⁷ ’;

-L ³ is selected from the group consisting of -O-, -CH2-, -S-, -NH-, S(O)i-2, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O) ₂ , and S(O) ₂ NH; each occurrence of R ⁷ ’ is independently selected from the group consisting of: halo; -CN; -NO2; -OH; -Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; -C2-4 alkenyl; -C2-4 alkynyl; -Ci-4 haloalkyl; -C1-6 alkoxy optionally substituted with 1- 2 independently selected R ^a ; -C1-6 haloalkoxy; S(O)i-2(Ci-4 alkyl); -NR’R”; oxo; -S(O)i- ₂ (NR’R”); -C1-4 thioalkoxy; -C(=O)(Ci- ₄ alkyl); -C(=O)O(Ci- ₄ alkyl); -C(=O)OH; and - C(=O)N(R’)(R”),

W is selected from the group consisting of:

(i) C(=O); (ii) C(=S); (iii) S(O)i- ₂ ; (iv) C(=NR ^d ) or C(=N-CN); (v) C(=NH); (vi) C(=C-NO ₂ ); (vii) S(=O)(=N(R ^d )); and (viii) S(=O)(=NH);

Q is selected from the group consisting of: NH, N(CI-6 alkyl), *-NH-(CI-3 alkylene)-, and *-N(CI-6 alkyl)-(Ci-3 alkylene)-, wherein the C1-6 alkyl is optionally substituted with 1-2 independently selected R ^a , and the asterisk represents point of attachment to W; each of R ^la , R ^lb , R ^lc , and R ^ld is independently selected from the group consisting of: H; halo; cyano; Ci-6 alkyl optionally substituted with 1-2 R ^a ; C2-6 alkenyl; C2-6 alkynyl; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -S(O)i-2(Ci-4 alkyl); -S(O)(=NH)(CI-4 alkyl); SF ₅ ; -NR ^e R ^f ; -OH; -S(O)I- ₂ (NR’R”); -Ci-4 thioalkoxy; -NO2; -C(=O)(Ci- ₄ alkyl); - C(=O)O(Ci-4 alkyl); -C(=O)OH; and -C(=O)N(R’)(R”); each occurrence of R ² is independently selected from the group consisting of:

(i) H;

(ii) C1-6 alkyl, which is optionally substituted with 1-3 independently selected R ^a ;

(iii) -C(O)(Ci-6 alkyl) optionally substituted with 1-3 independently selected R ^a ;

(iv) -C(O)O(Ci-4 alkyl) optionally substituted with 1-3 independently R ^a ;

(v) -CON(R’)(R”);

(vi) -S(O)I- ₂ (NR’R”);

(vii) - S(O)i-2(Ci-4 alkyl) optionally substituted with 1-3 independently selected R ^a ;

(viii) -OH;

(ix) Ci-4 alkoxy; and

(x) -L ⁴ -L ⁵ -R‘;

R ⁴ is selected from the group consisting of H and C1-6 alkyl optionally substituted with 1-3 independently selected R ^a ;

R ⁵ is selected from the group consisting of H; halo; -OH; -Ci-4 alkyl; -Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); - C(=O)OH; -CON(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci-4 alkyl); cyano; and C3-6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected Ci-4 alkyl;

R ⁶ is selected from the group consisting of H; C1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -OH; Ci-4 alkoxy; C(=O)H; C(=O)(Ci-4 alkyl); Ce-io aryl optionally substituted with 1-4 independently selected Ci-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Ci-4 alkyl; each occurrence of R ^a is independently selected from the group consisting of: - OH; -F; -Cl; -Br; -NR ^e R ^f ; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci- 4 alkyl); -C(=O)OH; -CON(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci- ₄ alkyl); cyano; and C ₃ - 6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected Ci-4 alkyl; each occurrence of R ^b is independently selected from the group consisting of: Ci- 10 alkyl optionally substituted with 1-6 independently selected R ^a ; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR ^e R ^f ; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-io alkyl); -C(=O)O(Ci- 4 alkyl); -C(=O)OH; -C(=O)N(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci-4 alkyl); cyano; and -L ¹ -L ² -R ^h ; each occurrence of R ^c is independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with 1-6 independently selected R ^a ; C ₂ -6 alkenyl; C ₂ -6 alkynyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -S(O)i- ₂ (Ci-4 alkyl); -NR ^e R ^f ; -OH; - S(O)I- ₂ (NR’R”); -CI-4 thioalkoxy; -NO ₂ ; -C(=0)(Ci-io alkyl); -C(=O)O(Ci- ₄ alkyl); - C(=O)OH; -C(=O)N(R’)(R”); and -L ¹ -L ² -R ^h ;

R ^d is selected from the group consisting of: C1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, C1-3 alkoxy, C1-3 haloalkoxy, and OH; C3-6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; -C(O)(Ci- ₄ alkyl); -C(O)O(Ci- ₄ alkyl); -CON(R’)(R”); -S(O)I- ₂ (NR’R”); - S(O)i- ₂ (Ci-4 alkyl); -OH; and Ci-4 alkoxy; each occurrence of R ^e and R ^f is independently selected from the group consisting of: H; C1-6 alkyl; C1-6 haloalkyl; C3-6 cycloalkyl or C3-6 cycloalkenyl; -C(O)(Ci-4 alkyl); - C(O)O(Ci-4 alkyl); -CON(R’)(R”); -S(O)I- ₂ (NR’R”); - S(O)i- ₂ (Ci-4 alkyl); -OH; and Ci-4 alkoxy; or

R ^e and R ^f together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R ^e and R ¹ ), which are each independently selected from the group consisting of N(R ^d ), NH, O, and S;

-L ¹ is a bond or C1-3 alkylene; -L ² is -O-, -N(H)-, -S(0)o-2-, or a bond;

R ^h is selected from the group consisting of:

• C3-8 cycloalkyl or C3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy;

• heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy; and

• Ce-io aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy;

-L ⁴ - is selected from the group consisting of a bond, -C(O)-, -C(O)O-, -C(O)NH-, C(O)NR ^d , S(O)i- ₂ , S(O)I- ₂ NH, and S(O)i- ₂ NR ^d ;

-L ⁵ - is selected from the group consisting of a bond and Ci-4 alkylene;

R‘ is selected from the group consisting of: • C3-8 cycloalkyl or C3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; OH; NR ^e R ^f ; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci- 4 alkoxy; and C 1-4 haloalkoxy;

• heterocyclyl or heterocycloalkenyl, wherein the heterocyclyl or heterocycloalkenyl has 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; OH; NR ^e R ^f ; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci- 4 alkoxy; and C 1-4 haloalkoxy;

• heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; OH; NR ^e R ^f ; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci-4 haloalkoxy; and

• Ce-io aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo; OH; NR ^e R ^f ; Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; Ci-4 haloalkyl; cyano; Ci-4 alkoxy; and Ci- 4 haloalkoxy; and each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; Ci-4 alkyl; Ce-io aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, Ci-4 alkyl, and Ci-4 haloalkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, -OH, NH2, NH(Ci-4 alkyl), N(CI-4 alkyl)2, Ci-4 alkyl, and Ci-4 haloalkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and Ci-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(H), N(CI-6 alkyl), O, and S.

In certain embodiments of Formula (M5), the compound is a compound of Formula

(M5-la), (M5-2a), or (M5-3a): or a pharmaceutically acceptable salt thereof, wherein: each of R ^la , R ^lb , R ^lc , R ^ld is independently selected from the group consisting of: H; halo; cyano; Ci-6 alkyl optionally substituted with 1-2 R ^a ; Ci-4 haloalkyl; Ci-4 alkoxy; and Ci-4 haloalkoxy; n2 is 0, 1, or 2; each R ^c when present is independently selected from the group consisting of: halo, cyano, C1-3 alkyl, and C1-3 alkoxy;

R ⁸ is selected from the group consisting of: wherein ml and m2 are independently 0, 1, or 2, and T ¹ is CH or N; and

• spirocyclic heterocyclyl of 6-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl ring is optionally substituted with 1-4 independently selected R ⁷ ’.

In some embodiments, the STING antagonist is a compound of Formula (M6): or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: each of Z, Y ¹ , Y ² , and Y ³ is independently selected from the group consisting of CR ¹ , N, and NR ² , provided that 1-3 of Z, Y ¹ , Y ² , and Y ³ is an independently selected N or NR ² ;

X ¹ is selected from the group consisting of O, S, N, NR ² , and CR ¹ ;

X ² is selected from the group consisting of O, S, N, NR ⁴ , and CR ⁵ ; each — is independently a single bond or a double bond, provided that the fivemembered ring comprising X ¹ and X ² is heteroaryl; the six-membered ring comprising Z, Y ¹ , Y ² , and Y ³ is heteroaryl; and the ring comprising P ¹ , P ² , P ³ , P ⁴ , and P ⁵ is aromatic;

W is selected from the group consisting of: (i) C(=O); (ii) C(=S); (iii) S(O)i-2; (iv) C(=NR ^d ) or C(=N-CN); (v) C(=NH); (vi) C(=C-NO ₂ ); (vii) S(=O)(=N(R ^d )); and (viii) S(=O)(=NH);

Q is selected from the group consisting of: NH, N(CI-6 alkyl), *-NH-(CI-3 alkylene)- , and *-N(CI-6 alkyl)-(Ci-3 alkylene)-, wherein the Ci-6 alkyl is optionally substituted with 1-2 independently selected R ^a , and the asterisk represents the point of attachment to W;

P ¹ , P ² , P ³ , P ⁴ , and P ⁵ are defined according to (AA) or (BB):

(AA) each of P ¹ , P ² , P ³ , P ⁴ , and P ⁵ is independently selected from the group consisting of: N, CH, CR ⁷ , and CR ^C , provided that: 1-2 of P ¹ , P ² , P ³ , P ⁴ , and P ⁵ is an independently selected CR ⁷ ; or

(BB) P ¹ is absent, thereby providing a 5-membered ring, each of P ² , P ³ , P ⁴ , and P ⁵ is independently selected from the group consisting of O, S, N, NH, NR ^d , NR ⁷ , CH, CR ⁷ , and CR ^C ; provided that 1-3 of P ² , P ³ , P ⁴ , and P ⁵ is O, S, N, NH, NR ^d , or NR ⁷ ; and

1-2 of P ² , P ³ , P ⁴ , and P ⁵ is an independently selected NR ⁷ or CR ⁷ ; each R ⁷ is independently selected from the group consisting of: -R ⁸ and -L ³ -R ⁹ ;

-R ⁸ is selected from the group consisting of:

(a) C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is substituted with 1-4 independently selected R ⁷ ’;

(b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is substituted with 1-4 independently selected R ⁷ ’;

(c) C3 cycloalkyl, C3 cycloalkenyl, C5 cycloalkyl, or C5 cycloalkenyl, each of which is optionally substituted with 1-4 independently selected Ci-4 alkyl;

(d) C7-12 cycloalkyl or C7-12 cycloalkenyl, each of which is optionally substituted with 1-4 independently selected Ci-4 alkyl;

(e) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2 provided that the heterocyclyl is other than tetrahydropyranyl, and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected Ci-4 alkyl;

(f) heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heteroaryl ring is optionally substituted with 1-4 independently selected R ⁷ ’; and

(g) Ce-io aryl optionally substituted with 1-4 independently selected R ⁷ ’;

-L ³ is selected from the group consisting of -O-, -S-, -NH-, S(O)i-2, -CH2-, C(=O)NH, NHC(=O), C(=O)O, OC(=O), C(=O), NHS(O) ₂ , and S(O) ₂ NH;

-R ⁹ is selected from the group consisting of: (a) C3-12 cycloalkyl or C3-12 cycloalkenyl, each of which is optionally substituted with 1-4 independently selected R ⁷ ’,

(b) heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R ⁷ ’;

(c) heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, and wherein one or more ring carbon atoms of the hetaroaryl ring is optionally substituted with 1-4 independently selected R ⁷ ’; and

(d) Ce-io aryl optionally substituted with 1-4 independently selected R ⁷ ’; each occurrence of R ⁷ ’ is independently selected from the group consisting of: halo; -CN; -NO2; -OH; -Ci-4 alkyl optionally substituted with 1-2 independently selected R ^a ; -C2-4 alkenyl; -C2-4 alkynyl; -Ci-4 haloalkyl; -C1-6 alkoxy optionally substituted with 1-2 independently selected R ^a ; -C1-6 haloalkoxy; S(O)i-2(Ci-4 alkyl); -NR’R”; oxo; - S(O)I- ₂ (NR’R”); -C1-4 thioalkoxy; -C(=O)(Ci- ₄ alkyl); -C(=O)O(Ci- ₄ alkyl); -C(=O)OH; and -C(=O)N(R’)(R”), provided that when R ⁷ is R ⁸ ; and R ⁸ is cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl and substituted with 1-4 R ⁷ ’, then:

R ⁸ cannot be monosubstituted with Ci-4 alkyl, and when R ⁸ is substituted with 2-4 R ⁷ ’, then at least one R ⁷ ’ must be a substituent other than Ci-4 alkyl; each occurrence of R ¹ is independently selected from the group consisting of:

H; halo; cyano; C1-6 alkyl optionally substituted with 1-2 R ^a ; C2-6 alkenyl; C2-6 alkynyl; Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -L ¹ -L ² -R ^h ; -S(O)i-2(Ci-4 alkyl); - S(O)(=NH)(C 1-4 alkyl); SF ₅ ; -NR ^e R ^f ; -OH; OXO;-S(O)I- ₂ (NR’R”); -Ci-4 thioalkoxy; -NO2; -C(=O)(Ci-4 alkyl); -C(=O)O(Ci- ₄ alkyl); -C(=O)OH; and -C(=0)N(R’)(R”); each occurrence of R ² is independently selected from the group consisting of:

(i) H;

(ii) C1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; (iii) -C(O)(Ci-6 alkyl) optionally substituted with 1-3 independently selected R ^a ;

(iv) -C(O)O(Ci-4 alkyl) optionally substituted with 1-3 independently selected R ^a ;

(v) -CON(R’)(R”);

(vi) -S(O)I- ₂ (NR’R”);

(vii) -S(O)i-2(Ci-4 alkyl) optionally substituted with 1-3 independently selected R ^a ;

(viii) -OH;

(ix) Ci-4 alkoxy; and

(x) -L ⁴ -L ⁵ -R‘;

R ⁴ is selected from the group consisting of H and Ci-6 alkyl optionally substituted with 1-3 independently selected R ^a ;

R ⁵ is selected from the group consisting of H; halo; -OH; -Ci-4 alkyl; -Ci-4 haloalkyl; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); - C(=O)OH; -CON(R’)(R”); -S(O)I- ₂ (NR’R”); -S(O)i- ₂ (Ci-4 alkyl); cyano; and C3-6 cycloalkyl or C3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected Ci-4 alkyl;

R ⁶ is selected from the group consisting of H; C1-6 alkyl optionally substituted with 1-3 independently selected R ^a ; -OH; Ci-4 alkoxy; C(=O)H; C(=O)(Ci-4 alkyl); Ce-io aryl optionally substituted with 1-4 independently selected Ci-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R ^d ), O, and S(0)o-2, wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Ci-4 alkyl; and each of R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , -L ¹ , -L ² , R ^h , -L ⁴ , L ⁵ , -R\ R’, and R” is as defined in Formula (M5) herein.

In certain embodiments of Formula (M6), the compound is a compound of Formula

(M6-3a) or (M6-3b): or a pharmaceutically acceptable salt thereof, wherein: each of R ^la , R ^lb , and R ^lc is independently selected from the group consisting of: H; halo; cyano; C1-6 alkyl optionally substituted with 1-2 R ^a ; Ci-4 haloalkyl; Ci-4 alkoxy; and Ci-4 haloalkoxy; Q ¹ is N or CH;

R ⁸ is selected from the group consisting of: n2 is 0, 1, or 2; each R ^c when present is independently selected from the group consisting of: halo, cyano, C1-3 alkyl, and C1-3 alkoxy; ml and m2 are independently 0, 1, or 2; m3, m4, m5, and m6 are independently 0 or 1; and

T ¹ is CH or N, optionally wherein R ² is H; optionally wherein n2 is 1, and R ^c is ortho to R ⁸ ; and optionally wherein each R ⁷ ’ is independently halo, such as -F.

In some embodiments, the STING antagonist is selected from the group consisting of the compounds in Table Cl, or a pharmaceutically acceptable salt thereof.

STING Inhibitory Nucleic Acids

In some embodiments of any of the methods described herein, the STING antagonist is an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is a short interfering RNA, an antisense nucleic acid, a cyclic dinucleotide, or a ribozyme.

Examples of aspects of these different oligonucleotides are described below. Any of the examples of inhibitory nucleic acids that are STING antagonists can decrease expression of STING mRNA in a mammalian cell (e.g., a human cell). Any of the inhibitory nucleic acids described herein can be synthesized in vitro.

Inhibitory nucleic acids that can decrease the expression of STING mRNA expression in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of a STING mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 1, 3, 5, or 7).

An antisense nucleic acid molecule can be complementary to all or part of a noncoding region of the coding strand of a nucleotide sequence encoding a STING protein. Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding a STING protein described herein. Antisense nucleic acids targeting a nucleic acid encoding a STING protein can be designed using the software available at the Integrated DNA Technologies website.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 1 -methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylguanine, 3 -methylcytosine, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5- fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4- acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2- thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D- galactosylqueosine, inosine, N6-isopentenyladenine, 5-methylcytosine, N6-adenine, 7- methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta- D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 5-methyl-2- thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, e.g., a human subject. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a STING protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An a- anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, P-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327- 330, 1987) or a 2'-O-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15:6131-6148, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding a STING mRNA, e.g., specificity for any one of SEQ ID NOs: 1, 3, 5, or 7). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. STING mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261 : 1411-1418, 1993.

Alternatively, a ribozyme having specificity for a STING mRNA sequence disclosed herein. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a STING mRNA (see, e.g., U.S. Patent. Nos. 4,987,071 and 5,116,742).

An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of a STING polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the STING polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Maher, Bioassays 14(12): 807- 15, 1992; Helene, Anticancer Drug Des. 6(6):569- 84, 1991; and Helene, Ann. N.Y. Acad. Sci. 660:27-36, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, the base moiety, or phosphate backbone to improve, e.g., the solubility, stability, or hybridization, of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al., Bioorganic Medicinal Chem. 4(l):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al., Proc. Natl. Acad. Sci. U.S.A. 93: 14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. cGAS Inhibitors

In any of the methods described herein, the cGAS inhibitors can be any of the cGAS inhibitors described herein (e.g., any of the compounds described in this section). In any of the methods described herein, the cGAS inhibitorhas an ICso of between about 1 nM and about 10 pM for cGAS. In one aspect, the cGAS inhibitor is a compound selected from the group consisting of compounds in Table C2 and pharmaceutically acceptable salts thereof.

Table C2 In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in US Provisional 62/355,403, filed on Jun. 28, 2016, which is incorporated herein by reference in its entirety.

In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in US Provisional 62/318,435, filed on Apr. 5, 2016, which is incorporated herein by reference in its entirety. In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in US Application 2018/0230115 Al, published Aug. 16, 2018, which is incorporated herein by reference in its entirety.

In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in Vincent, J. et al. (2017) Nat. Commun. 8(l):750, which is incorporated herein by reference in its entirety.

In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in Hall, J. et al. (2017) PLOS ONE 12(9):el84843, which is incorporated herein by reference in its entirety.

In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in Wang, M. et al. (2018) Future Med. Chem. 10(11): 1301-17, which is incorporated herein by reference in its entirety.

In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in US Provisional 62/559,482, filed on Sep. 15, 2017, which is incorporated herein by reference in its entirety.

In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in US Provisional 62/633,248, filed on Feb. 21, 2018, which is incorporated herein by reference in its entirety.

In some embodiments, the cGAS inhibitor is selected from the compounds disclosed in US Provisional 62/687,769, filed on June 20, 2018, which is incorporated herein by reference in its entirety.

Pharmaceutical Compositions

In some embodiments, a STING antagonist or cGAS inhibitor (e.g., any of the STING antagonists or cGAS inhibitors described herein or known in the art) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the STING antagonist or cGAS inhibitor can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, 0, and y- cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of the STING antagonists or cGAS inhibitors described herein. Dosage forms or compositions containing a STING antagonist or cGAS inhibitor as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a STING antagonist, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22 ^nd Edition (Pharmaceutical Press, London, UK. 2012).

Routes of Administration and Composition Components

In some embodiments, the STING antagonist or cGAS inhibitor (e.g., any of the exemplary STING antagonists or cGAS inhibitors described herein or known in the art) or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensionhs; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the STING antagonist or cGAS inhibitor in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.

In certain embodiments, the STING antagonist or cGAS inhibitor or a pharmaceutical composition thereof are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).

Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy -metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

In certain embodiments, suppositories can be prepared by mixing the STING antagonist or cGAS inhibitor with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

In other embodiments, the STING antagonist or cGAS inhibitor or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the STING antagonist or cGAS inhibitor is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a STING antagonist or cGAS inhibitor, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more STING antagonists or cGAS inhibitors or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments, the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the STING antagonist or cGAS inhibitor to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the STING antagonist or cGAS inhibitor are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers. Enema Formulations

In some embodiments, enema formulations containing a STING antagonist or cGAS inhibitor are provided in "ready-to-use" form.

In some embodiments, enema formulations containing a STING antagonist or cGAS inhibitor are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two or more separately contained/packaged components, e.g. two components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the STING antagonist or cGAS inhibitor (as described anywhere herein) and optionally one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and optionally one or more other pharmaceutically acceptable excipients together forming a liquid carrier. Prior to use (e.g., immediately prior to use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.

In some embodiments, each of the one or more liquids is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents. Typical such solvents include, without limitation, glycerol, ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. In certain embodiments, each of the one or more liquids is water. In other embodiments, each of the one or more liquids is an oil, e.g. natural and/or synthetic oils that are commonly used in pharmaceutical preparations.

Further pharmaceutical excipients and carriers that may be used in the pharmaceutical products herein described are listed in various handbooks (e.g. D. E. Bugay and W. P. Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999), E- M Hoepfner, A. Reng and P. C. Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and H. P. Fielder (Ed) Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete (Edition Cantor Aulendorf, 1989)).

In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhanceers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, anti-oxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonic agents, chelating agents, emulsifiers, and diagnostic agents.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers.

In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from diluents, binders, lubricants, glidants, and disintegrants.

Examples of thickeners, viscosity enhancing agents, and mucoadhesive agents include without limitation: gums, e.g. xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psyllium seed gum and gum arabic; poly(carboxylic acid-containing) based polymers, such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic or methacrylic) acid which have strong hydrogenbonding groups, or derivatives thereof such as salts and esters; cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof; clays such as manomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharides such as dextran, pectin, amylopectin, agar, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan, e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate; schleroglucan; adhesives containing bismuth oxide or aluminium oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinyl chlorides, polyvinylidenes, and/or the like; polycarboxylated vinyl polymers such as polyacrylic acid as mentioned above; polysiloxanes; polyethers; polyethylene oxides and glycols; polyalkoxys and polyacrylamides and derivatives and salts thereof. Preferred examples can include cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone).

Examples of preservatives include without limitation: benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®), Polyquart®), and sodium perborate tetrahydrate and the like.

In certain embodiments, the preservative is a paraben, or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl substituted 4- hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof. Examples of buffers include without limitation: phosphate buffer system (sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer system, and bisulfate buffer system.

Examples of disintegrants include, without limitation: carmellose calcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, carboxymethyl starch sodium, crospovidone, polysorbate 80 (polyoxyethylenesorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp). In certain embodiments, the disintegrant is crospovidone.

Examples of glidants and lubricants (aggregation inhibitors) include without limitation: talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium laurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid glycerol behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant/lubricant is magnesium stearate, talc, and/or colloidal silica; e.g., magnesium stearate and/or talc.

Examples of diluents, also referred to as “fillers” or “bulking agents” include without limitation: dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).

Examples of binders include without limitation: starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dxtrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia tragacanth, sodium alginate cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).

In some embodiments, enema formulations containing a STING antagonist or cGAS inhibitor include water and one or more (e.g., all) of the following excipients:

One or more (e.g., one, two, or three) thickeners, viscosity enhancing agents, binders, and/or mucoadhesive agents (e.g., cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone);

One or more (e.g., one or two; e.g., two) preservatives, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof;

One or more (e.g., one or two; e.g., two) buffers, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate);

One or more (e.g., one or two, e.g., two) glidants and/or lubricants, such as magnesium stearate and/or talc;

One or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and

One or more (e.g., one or two; e.g., one) diluents, such as lactose (e.g., lactose monohydrate).

In certain of these embodiments, the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6 or a compound shown in any one of Table Cl, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.

In certain embodiments, enema formulations containing a STING antagonist or cGAS inhibitor include water, methyl cellulose, povidone, methylparaben, propylparaben, sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, crospovidone, lactose monohydrate, magnesium stearate, and talc. In certain of these embodiments, the STING antagonist is a compound of any one of Formulas I-XXIV or Formulas M1-M6 or a compound shown in any one of Table Cl, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. In certain embodiments, enema formulations containing a STING antagonist or cGAS inhibitor are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two separately contained/packaged components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the STING antagonist or cGAS inhibitor (as described anywhere herein) and one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and one or more one or more other pharmaceutically acceptable excipients together forming a liquid carrier. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.

In certain of these embodiments, component (i) includes the STING antagonist or cGAS inhibitor (e.g., a compound of any one of Formulas I-XXIV or Formulas M1-M6 or a compound shown in any one of Tables C1-C2, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) and one or more (e.g., all) of the following excipients:

(a) One or more (e.g., one) binders (e.g., a polyvinyl polymer, such as polyvinylpyrrolidone (povidone);

(b) One or more (e.g., one or two, e.g., two) glidants and/or lubricants, such as magnesium stearate and/or talc;

(c) One or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and

(d) One or more (e.g., one or two; e.g., one) diluents, such as lactose (e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 40 weight percent to about 80 weight percent (e.g., from about 50 weight percent to about 70 weight percent, from about 55 weight percent to about 70 weight percent; from about 60 weight percent to about 65 weight percent; e.g., about 62.1 weight percent) of the STING antagonist or cGAS inhibitor (e.g., a compound of any one of Formulas I-XXIV or Formulas M1-M6 or a compound shown in any one of Tables C1-C2, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof).

In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 1.5 weight percent to about 4.5 weight percent, from about 2 weight percent to about 3.5 weight percent; e.g., about 2.76 weight percent) of the binder (e.g., povidone).

In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; about 2 weight percent e.g., about 1.9 weight percent) of the disintegrant (e.g., crospovidone).

In certain embodiments, component (i) includes from about 10 weight percent to about 50 weight percent (e.g., from about 20 weight percent to about 40 weight percent, from about 25 weight percent to about 35 weight percent; e.g., about 31.03 weight percent) of the diluent (e.g., lactose, e.g., lactose monohydrate).

In certain embodiments, component (i) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent) of the glidants and/or lubricants.

In certain embodiments (e.g., when component (i) includes one or more lubricants, such as magnesium stearate), component (i) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 1 weight percent; from about 0.1 weight percent to about 1 weight percent; from about 0.1 weight percent to about 0.5 weight percent; e.g., about 0.27 weight percent) of the lubricant (e.g., magnesium stearate).

In certain embodiments (when component (i) includes one or more lubricants, such as talc), component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; from about 1.5 weight percent to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent; about 1.93 weight percent) of the lubricant (e.g., talc). In certain of these embodiments, each of (a), (b), (c), and (d) above is present.

In certain embodiments, component (i) includes the ingredients and amounts as shown in Table A.

In certain embodiments, component (i) includes the ingredients and amounts as shown in Table B. Table B

In certain embodiments, component (i) is formulated as a wet granulated solid preparation. In certain of these embodiments an internal phase of ingredients (the STING antagonist or cGAS inhibitor, disintegrant, and diluent) are combined and mixed in a high- shear granulator. A binder (e.g., povidone) is dissolved in water to form a granulating solution. This solution is added to the Inner Phase mixture resulting in the development of granules. While not wishing to be bound by theory, granule development is believed to be facilitated by the interaction of the polymeric binder with the materials of the internal phase. Once the granulation is formed and dried, an external phase (e.g., one or more lubricants - not an intrinsic component of the dried granulation), is added to the dry granulation. It is believed that lubrication of the granulation is important to the flowability of the granulation, in particular for packaging.

In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

(a’) One or more (e.g., one, two; e.g., two) thickeners, viscosity enhancing agents, binders, and/or mucoadhesive agents (e.g., cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone);

(b’) One or more (e.g., one or two; e.g., two) preservatives, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof; and

(c’) One or more (e.g., one or two; e.g., two) buffers, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dihydrate, disodium phosphate dodecahydrate);

In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

(a”) a first thickener, viscosity enhancing agent, binder, and/or mucoadhesive agent (e.g., a cellulose or cellulose ester or ether or derivative or salt thereof (e.g., methyl cellulose));

(a’”) a second thickener, viscosity enhancing agent, binder, and/or mucoadhesive agent (e.g., a polyvinyl polymer, such as polyvinylpyrrolidone (povidone));

(b”) a first preservative, such as a paraben, e.g., propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof; (b”) a second preservative, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof,

(c”) a first buffer, such as phosphate buffer system (e.g., disodium phosphate dodecahydrate);

(c’”) a second buffer, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dehydrate),

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 3 weight percent; e.g., about 1.4 weight percent) of (a”).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent; e.g., about 1.0 weight percent) of (a’”).

In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.1 weight percent (e.g., from about 0.005 weight percent to about 0.05 weight percent; e.g., about 0.02 weight percent) of (b”).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.20 weight percent) of (b’”).

In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.15 weight percent) of (c”).

In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.5 weight percent (e.g., from about 0.005 weight percent to about 0.3 weight percent; e.g., about 0.15 weight percent) of (c’”).

In certain of these embodiments, each of (a”) - (c’”) is present.

In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table C.

In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table D. Table D

“Ready -to-use" enemas are generally be provided in a "single-use" sealed disposable container of plastic or glass. Those formed of a polymeric material preferably have sufficient flexibility for ease of use by an unassisted patient. Typical plastic containers can be made of polyethylene. These containers may comprise a tip for direct introduction into the rectum. Such containers may also comprise a tube between the container and the tip. The tip is preferably provided with a protective shield that is removed before use. Optionally the tip has a lubricant to improve patient compliance.

In some embodiments, the enema formulation (e.g., suspension) is poured into a bottle for delivery after it has been prepared in a separate container. In certain embodiments, the bottle is a plastic bottle (e.g., flexible to allow for delivery by squeezing the bottle), which can be a polyethylene bottle (e.g., white in color). In some embodiments, the bottle is a single chamber bottle, which contains the suspension or solution. In other embodiments, the bottle is a multichamber bottle, where each chamber contains a separate mixture or solution. In still other embodiments, the bottle can further include a tip or rectal cannula for direct introduction into the rectum. In some embodiments, the enema formulation can be delivered in the device that includes a plastic bottle, a breakable capsule, and a rectal cannula and single flow pack.

Dosages

The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

In some embodiments, the STING antagonist or cGAS inhibitor is administered at a dosage of from about 0.001 mg/kg to about 500 mg/kg.

In some embodiments, enema formulations include from about 0.5 mg to about 2500 mg of the chemical entity in from about 1 mL to about 3000 mL of liquid carrier.

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

In some embodiments, the period of administration of a STING antagonist or cGAS inhibitor is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a STING antagonist or cGAS inhibitor is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a STING antagonist or cGAS inhibitor is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the STING antagonist or cGAS inhibitor is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a STING antagonist or cGAS inhibitor followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

Kits

Also provided herein are kits containing one or more (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18, or 20) of any of the pharmaceutical compositions described herein. In some embodiments, the kits can include instructions for performing any of the methods described herein. In some embodiments, the kits can include at least one dose of any of the compositions (e.g., pharmaceutical compositions) described herein. In some embodiments, the kits can provide a syringe for administering any of the pharmaceutical compositions described herein. The kits described herein are not so limited; other variations will be apparent to one of ordinary skill in the art.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Sequence Appendix

Human STING cDNA, Variant 1 (SEQ ID NO: 1)

ATGCCCCACTCCAGCCTGCATCCATCCATCCCGTGTCCCAGGGGTCACGGGG CCCAGAAGGCAGCCTTGGTTCTGCTGAGTGCCTGCCTGGTGACCCTTTGGGGG CTAGGAGAGCCACCAGAGCACACTCTCCGGTACCTGGTGCTCCACCTAGCCT CCCTGCAGCTGGGACTGCTGTTAAACGGGGTCTGCAGCCTGGCTGAGGAGCT GCGCCACATCCACTCCAGGTACCGGGGCAGCTACTGGAGGACTGTGCGGGCC TGCCTGGGCTGCCCCCTCCGCCGTGGGGCCCTGTTGCTGCTGTCCATCTATTT CTACTACTCCCTCCCAAATGCGGTCGGCCCGCCCTTCACTTGGATGCTTGCCC TCCTGGGCCTCTCGCAGGCACTGAACATCCTCCTGGGCCTCAAGGGCCTGGC CCCAGCTGAGATCTCTGCAGTGTGTGAAAAAGGGAATTTCAACGTGGCCCAT GGGCTGGCATGGTCATATTACATCGGATATCTGCGGCTGATCCTGCCAGAGCT CCAGGCCCGGATTCGAACTTACAATCAGCATTACAACAACCTGCTACGGGGT GCAGTGAGCCAGCGGCTGTATATTCTCCTCCCATTGGACTGTGGGGTGCCTGA TAACCTGAGTATGGCTGACCCCAACATTCGCTTCCTGGATAAACTGCCCCAGC AGACCGGTGACCATGCTGGCATCAAGGATCGGGTTTACAGCAACAGCATCTA TGAGCTTCTGGAGAACGGGCAGCGGGCGGGCACCTGTGTCCTGGAGTACGCC ACCCCCTTGCAGACTTTGTTTGCCATGTCACAATACAGTCAAGCTGGCTTTAG CCGGGAGGATAGGCTTGAGCAGGCCAAACTCTTCTGCCGGACACTTGAGGAC ATCCTGGCAGATGCCCCTGAGTCTCAGAACAACTGCCGCCTCATTGCCTACCA GGAACCTGCAGATGACAGCAGCTTCTCGCTGTCCCAGGAGGTTCTCCGGCAC

CTGCGGCAGGAGGAAAAGGAAGAGGTTACTGTGGGCAGCTTGAAGACCTCA GCGGTGCCCAGTACCTCCACGATGTCCCAAGAGCCTGAGCTCCTCATCAGTG GAATGGAAAAGCCCCTCCCTCTCCGCACGGATTTCTCTTGA

Human STING Protein, Variant 1 (SEQ ID NO: 2)

MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQ LGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLP NAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYY IGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIR FLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQY SQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVL RHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS

Human STING cDNA, Variant 2 (SEQ ID NO: 3)

ATGCCCCACTCCAGCCTGCATCCATCCATCCCGTGTCCCAGGGGTCACGGGG CCCAGAAGGCAGCCTTGGTTCTGCTGAGTGCCTGCCTGGTGACCCTTTGGGGG CTAGGAGAGCCACCAGAGCACACTCTCCGGTACCTGGTGCTCCACCTAGCCT CCCTGCAGCTGGGACTGCTGTTAAACGGGGTCTGCAGCCTGGCTGAGGAGCT GCGCCACATCCACTCCAGGTACCGGGGCAGCTACTGGAGGACTGTGCGGGCC TGCCTGGGCTGCCCCCTCCGCCGTGGGGCCCTGTTGCTGCTGTCCATCTATTT

CTACTACTCCCTCCCAAATGCGGTCGGCCCGCCCTTCACTTGGATGCTTGCCC

TCCTGGGCCTCTCGCAGGCACTGAACATCCTCCTGGGCCTCAAGGGCCTGGC

CCCAGCTGAGATCTCTGCAGTGTGTGAAAAAGGGAATTTCAACGTGGCCCAT

GGGCTGGCATGGTCATATTACATCGGATATCTGCGGCTGATCCTGCCAGAGCT

CCAGGCCCGGATTCGAACTTACAATCAGCATTACAACAACCTGCTACGGGGT

GCAGTGAGCCAGCGGCTGTATATTCTCCTCCCATTGGACTGTGGGGTGCCTGA

TAACCTGAGTATGGCTGACCCCAACATTCGCTTCCTGGATAAACTGCCCCAGC

AGACCGGTGACCATGCTGGCATCAAGGATCGGGTTTACAGCAACAGCATCTA TGAGCTTCTGGAGAACGGGCAGCGGAACCTGCAGATGACAGCAGCTTCTCGC

TGTCCCAGGAGGTTCTCCGGCACCTGCGGCAGGAGGAAAAGGAAGAGGTTAC TGTGGGCAGCTTGA

Human STING Protein, Variant 2 (SEQ ID NO: 4)

MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQ

LGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLP

NAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYY IGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIR FLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRNLQMTAASRCPRRFSGTCGRR KRKRLLWAA

Human STING cDNA, Variant 3 Precursor (SEQ ID NO: 5)

ATGCTTGCCCTCCTGGGCCTCTCGCAGGCACTGAACATCCTCCTGGGCCTCAA

GGGCCTGGCCCCAGCTGAGATCTCTGCAGTGTGTGAAAAAGGGAATTTCAAC

GTGGCCCATGGGCTGGCATGGTCATATTACATCGGATATCTGCGGCTGATCCT

GCCAGAGCTCCAGGCCCGGATTCGAACTTACAATCAGCATTACAACAACCTG

CTACGGGGTGCAGTGAGCCAGCGGCTGTATATTCTCCTCCCATTGGACTGTGG

GGTGCCTGATAACCTGAGTATGGCTGACCCCAACATTCGCTTCCTGGATAAAC

TGCCCCAGCAGACCGGTGACCATGCTGGCATCAAGGATCGGGTTTACAGCAA

CAGCATCTATGAGCTTCTGGAGAACGGGCAGCGGGCGGGCACCTGTGTCCTG

GAGTACGCCACCCCCTTGCAGACTTTGTTTGCCATGTCACAATACAGTCAAGC

TGGCTTTAGCCGGGAGGATAGGCTTGAGCAGGCCAAACTCTTCTGCCGGACA

CTTGAGGACATCCTGGCAGATGCCCCTGAGTCTCAGAACAACTGCCGCCTCA

TTGCCTACCAGGAACCTGCAGATGACAGCAGCTTCTCGCTGTCCCAGGAGGT

TCTCCGGCACCTGCGGCAGGAGGAAAAGGAAGAGGTTACTGTGGGCAGCTTG

AAGACCTCAGCGGTGCCCAGTACCTCCACGATGTCCCAAGAGCCTGAGCTCC

TCATCAGTGGAATGGAAAAGCCCCTCCCTCTCCGCACGGATTTCTCTTGA

Human STING Protein, Variant 3 Precursor (SEQ ID NO: 6)

MLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPE LQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQT GDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSRED RLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKE

EVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS

Human STING cDNA, Variant 3 Mature Sequence (SEQ ID NO: 7)

CTCAAGGGCCTGGCCCCAGCTGAGATCTCTGCAGTGTGTGAAAAAGGGAATT

TCAACGTGGCCCATGGGCTGGCATGGTCATATTACATCGGATATCTGCGGCTG

ATCCTGCCAGAGCTCCAGGCCCGGATTCGAACTTACAATCAGCATTACAACA

ACCTGCTACGGGGTGCAGTGAGCCAGCGGCTGTATATTCTCCTCCCATTGGAC

TGTGGGGTGCCTGATAACCTGAGTATGGCTGACCCCAACATTCGCTTCCTGGA

TAAACTGCCCCAGCAGACCGGTGACCATGCTGGCATCAAGGATCGGGTTTAC

AGCAACAGCATCTATGAGCTTCTGGAGAACGGGCAGCGGGCGGGCACCTGTG

TCCTGGAGTACGCCACCCCCTTGCAGACTTTGTTTGCCATGTCACAATACAGT

CAAGCTGGCTTTAGCCGGGAGGATAGGCTTGAGCAGGCCAAACTCTTCTGCC

GGACACTTGAGGACATCCTGGCAGATGCCCCTGAGTCTCAGAACAACTGCCG

CCTCATTGCCTACCAGGAACCTGCAGATGACAGCAGCTTCTCGCTGTCCCAG

GAGGTTCTCCGGCACCTGCGGCAGGAGGAAAAGGAAGAGGTTACTGTGGGC

AGCTTGAAGACCTCAGCGGTGCCCAGTACCTCCACGATGTCCCAAGAGCCTG

AGCTCCTCATCAGTGGAATGGAAAAGCCCCTCCCTCTCCGCACGGATTTCTCT TGA

Human STING Protein, Variant 3 Mature Sequence (SEQ ID NO: 8)

LKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLL

RGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIY

ELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILA

DAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTST MSQEPELLISGMEKPLPLRTDF S

Human TREX1 cDNA Sequence, Variant 1 (SEQ ID NO: 9)

ATGGGCTCGCAGGCCCTGCCCCCGGGGCCCATGCAGACCCTCATCTTTTTCGA

CATGGAGGCCACTGGCTTGCCCTTCTCCCAGCCCAAGGTCACGGAGCTGTGC

CTGCTGGCTGTCCACAGATGTGCCCTGGAGAGCCCCCCCACCTCTCAGGGGC

CACCTCCCACAGTTCCTCCACCACCGCGTGTGGTAGACAAGCTCTCCCTGTGT

GTGGCTCCGGGGAAGGCCTGCAGCCCTGCAGCCAGCGAGATCACAGGTCTGA

GCACAGCTGTGCTGGCAGCGCATGGGCGTCAATGTTTTGATGACAACCTGGC

CAACCTGCTCCTAGCCTTCCTGCGGCGCCAGCCACAGCCCTGGTGCCTGGTGG

CACACAATGGTGACCGCTACGACTTCCCCCTGCTCCAAGCAGAGCTGGCTAT

GCTGGGCCTCACCAGTGCTCTGGATGGTGCCTTCTGTGTGGATAGCATCACTG

CGCTGAAGGCCCTGGAGCGAGCAAGCAGCCCCTCAGAACACGGCCCAAGGA

AGAGCTATAGCCTAGGCAGCATCTACACTCGCCTGTATGGGCAGTCCCCTCC

AGACTCGCACACGGCTGAGGGTGATGTCCTGGCCCTGCTCAGCATCTGTCAG

TGGAGACCACAGGCCCTGCTGCGGTGGGTGGATGCTCACGCCAGGCCTTTCG

GCACCATCAGGCCCATGTATGGGGTCACAGCCTCTGCTAGGACCAAGCCAAG ACCATCTGCTGTCACAACCACTGCACACCTGGCCACAACCAGGAACACTAGT CCCAGCCTTGGAGAGAGCAGGGGTACCAAGGATCTTCCTCCAGTGAAGGACC CTGGAGCCCTATCCAGGGAGGGGCTGCTGGCCCCACTGGGTCTGCTGGCCAT

CCTGACCTTGGCAGTAGCCACACTGTATGGACTATCCCTGGCCACACCTGGG GAGTAG

Human TREX1 Protein Sequence, Variant 1 (SEQ ID NO: 10)

MGSQALPPGPMQTLIFFDMEATGLPFSQPKVTELCLLAVHRCALESPPTSQGPPPT

VPPPPRVVDKLSLCVAPGKACSPAASEITGLSTAVLAAHGRQCFDDNLANLLLAF

LRRQPQPWCLVAHNGDRYDFPLLQAELAMLGLTSALDGAFCVDSITALKALERA

SSPSEHGPRKSYSLGSIYTRLYGQSPPDSHTAEGDVLALLSICQWRPQALLRWVD

AHARPFGTIRPMYGVTASARTKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPP VKDPGALSREGLLAPLGLLAILTLAVATLYGLSLATPGE

Human TREX1 cDNA Sequence, Variant 2 (SEQ ID NO: 11)

ATGCAGACCCTCATCTTTTTCGACATGGAGGCCACTGGCTTGCCCTTCTCCCA GCCCAAGGTCACGGAGCTGTGCCTGCTGGCTGTCCACAGATGTGCCCTGGAG AGCCCCCCCACCTCTCAGGGGCCACCTCCCACAGTTCCTCCACCACCGCGTGT

GGTAGACAAGCTCTCCCTGTGTGTGGCTCCGGGGAAGGCCTGCAGCCCTGCA GCCAGCGAGATCACAGGTCTGAGCACAGCTGTGCTGGCAGCGCATGGGCGTC AATGTTTTGATGACAACCTGGCCAACCTGCTCCTAGCCTTCCTGCGGCGCCAG

CCACAGCCCTGGTGCCTGGTGGCACACAATGGTGACCGCTACGACTTCCCCC

TGCTCCAAGCAGAGCTGGCTATGCTGGGCCTCACCAGTGCTCTGGATGGTGC CTTCTGTGTGGATAGCATCACTGCGCTGAAGGCCCTGGAGCGAGCAAGCAGC CCCTCAGAACACGGCCCAAGGAAGAGCTATAGCCTAGGCAGCATCTACACTC

GCCTGTATGGGCAGTCCCCTCCAGACTCGCACACGGCTGAGGGTGATGTCCT

GGCCCTGCTCAGCATCTGTCAGTGGAGACCACAGGCCCTGCTGCGGTGGGTG

GATGCTCACGCCAGGCCTTTCGGCACCATCAGGCCCATGTATGGGGTCACAG

CCTCTGCTAGGACCAAGCCAAGACCATCTGCTGTCACAACCACTGCACACCT

GGCCACAACCAGGAACACTAGTCCCAGCCTTGGAGAGAGCAGGGGTACCAA GGATCTTCCTCCAGTGAAGGACCCTGGAGCCCTATCCAGGGAGGGGCTGCTG GCCCCACTGGGTCTGCTGGCCATCCTGACCTTGGCAGTAGCCACACTGTATGG

ACTATCCCTGGCCACACCTGGGGAGTAG

Human TREX1 Protein Sequence, Variant 2 (SEQ ID NO: 12)

MQTLIFFDMEATGLPFSQPKVTELCLLAVHRCALESPPTSQGPPPTVPPPPRVVDK

LSLCVAPGKACSPAASEITGLSTAVLAAHGRQCFDDNLANLLLAFLRRQPQPWC

LVAHNGDRYDFPLLQAELAMLGLTSALDGAFCVDSITALKALERASSPSEHGPR

KSYSLGSIYTRLYGQSPPDSHTAEGDVLALLSICQWRPQALLRWVDAHARPFGTI RPMYGVTASARTKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPVKDPGALSR EGLLAPLGLLAILTLAVATLYGLSLATPGE Human TREX Protein Sequence, Variant 3 (SEQ ID NO: 13)

MGPGARRQGRIVQGRPEMCFCPPPTPLPPLRILTLGTHTPTPCSSPGSAAGTYPTM

GSQALPPGPMQTLIFFDMEATGLPFSQPKVTELCLLAVHRCALESPPTSQGPPPTV

PPPPRVVDKLSLCVAPGKACSPAASEITGLSTAVLAAHGRQCFDDNLANLLLAFL

RRQPQPWCLVAHNGDRYDFPLLQAELAMLGLTSALDGAFCVDSITALKALERAS

SPSEHGPRKSYSLGSIYTRLYGQSPPDSHTAEGDVLALLSICQWRPQALLRWVDA

HARPFGTIRPMYGVTASARTKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPV

KDPGALSREGLLAPLGLLAILTLAVATLYGLSLATPGE

Human BRCA1 cDNA Sequence, Variant 1 (SEQ ID NO: 14)

ATGGATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAATGCTAT

GCAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATCAAGGAACCTGTCT

CCACAAAGTGTGACCACATATTTTGCAAATTTTGCATGCTGAAACTTCTCAAC

CAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGATATAACCAAAA

GGAGCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTGAAGAGCTATTGAA

AATCATTTGTGCTTTTCAGCTTGACACAGGTTTGGAGTATGCAAACAGCTATA

ATTTTGCAAAAAAGGAAAATAACTCTCCTGAACATCTAAAAGATGAAGTTTC

TATCATCCAAAGTATGGGCTACAGAAACCGTGCCAAAAGACTTCTACAGAGT

GAACCCGAAAATCCTTCCTTGCAGGAAACCAGTCTCAGTGTCCAACTCTCTA

ACCTTGGAACTGTGAGAACTCTGAGGACAAAGCAGCGGATACAACCTCAAAA

GACGTCTGTCTACATTGAATTGGGATCTGATTCTTCTGAAGATACCGTTAATA

AGGCAACTTATTGCAGTGTGGGAGATCAAGAATTGTTACAAATCACCCCTCA

AGGAACCAGGGATGAAATCAGTTTGGATTCTGCAAAAAAGGCTGCTTGTGAA

TTTTCTGAGACGGATGTAACAAATACTGAACATCATCAACCCAGTAATAATG

ATTTGAACACCACTGAGAAGCGTGCAGCTGAGAGGCATCCAGAAAAGTATCA

GGGTAGTTCTGTTTCAAACTTGCATGTGGAGCCATGTGGCACAAATACTCATG

CCAGCTCATTACAGCATGAGAACAGCAGTTTATTACTCACTAAAGACAGAAT

GAATGTAGAAAAGGCTGAATTCTGTAATAAAAGCAAACAGCCTGGCTTAGCA

AGGAGCCAACATAACAGATGGGCTGGAAGTAAGGAAACATGTAATGATAGG

CGGACTCCCAGCACAGAAAAAAAGGTAGATCTGAATGCTGATCCCCTGTGTG

AGAGAAAAGAATGGAATAAGCAGAAACTGCCATGCTCAGAGAATCCTAGAG

ATACTGAAGATGTTCCTTGGATAACACTAAATAGCAGCATTCAGAAAGTTAA

TGAGTGGTTTTCCAGAAGTGATGAACTGTTAGGTTCTGATGACTCACATGATG

GGGAGTCTGAATCAAATGCCAAAGTAGCTGATGTATTGGACGTTCTAAATGA

GGTAGATGAATATTCTGGTTCTTCAGAGAAAATAGACTTACTGGCCAGTGAT

CCTCATGAGGCTTTAATATGTAAAAGTGAAAGAGTTCACTCCAAATCAGTAG

AGAGTAATATTGAAGACAAAATATTTGGGAAAACCTATCGGAAGAAGGCAA

GCCTCCCCAACTTAAGCCATGTAACTGAAAATCTAATTATAGGAGCATTTGTT

ACTGAGCCACAGATAATACAAGAGCGTCCCCTCACAAATAAATTAAAGCGTA

AAAGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAGAAAGCAGA

TTTGGCAGTTCAAAAGACTCCTGAAATGATAAATCAGGGAACTAACCAAACG

GAGCAGAATGGTCAAGTGATGAATATTACTAATAGTGGTCATGAGAATAAAA

CAAAAGGTGATTCTATTCAGAATGAGAAAAATCCTAACCCAATAGAATCACT CGAAAAAGAATCTGCTTTCAAAACGAAAGCTGAACCTATAAGCAGCAGTATA

AGCAATATGGAACTCGAATTAAATATCCACAATTCAAAAGCACCTAAAAAGA

ATAGGCTGAGGAGGAAGTCTTCTACCAGGCATATTCATGCGCTTGAACTAGT

AGTCAGTAGAAATCTAAGCCCACCTAATTGTACTGAATTGCAAATTGATAGTT

GTTCTAGCAGTGAAGAGATAAAGAAAAAAAAGTACAACCAAATGCCAGTCA

GGCACAGCAGAAACCTACAACTCATGGAAGGTAAAGAACCTGCAACTGGAG

CCAAGAAGAGTAACAAGCCAAATGAACAGACAAGTAAAAGACATGACAGCG

ATACTTTCCCAGAGCTGAAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGT

TCAAATACCAGTGAACTTAAAGAATTTGTCAATCCTAGCCTTCCAAGAGAAG

AAAAAGAAGAGAAACTAGAAACAGTTAAAGTGTCTAATAATGCTGAAGACC

CCAAAGATCTCATGTTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTGT

AGAGAGTAGCAGTATTTCATTGGTACCTGGTACTGATTATGGCACTCAGGAA

AGTATCTCGTTACTGGAAGTTAGCACTCTAGGGAAGGCAAAAACAGAACCAA

ATAAATGTGTGAGTCAGTGTGCAGCATTTGAAAACCCCAAGGGACTAATTCA

TGGTTGTTCCAAAGATAATAGAAATGACACAGAAGGCTTTAAGTATCCATTG

GGACATGAAGTTAACCACAGTCGGGAAACAAGCATAGAAATGGAAGAAAGT

GAACTTGATGCTCAGTATTTGCAGAATACATTCAAGGTTTCAAAGCGCCAGTC

ATTTGCTCCGTTTTCAAATCCAGGAAATGCAGAAGAGGAATGTGCAACATTC

TCTGCCCACTCTGGGTCCTTAAAGAAACAAAGTCCAAAAGTCACTTTTGAATG

TGAACAAAAGGAAGAAAATCAAGGAAAGAATGAGTCTAATATCAAGCCTGT

ACAGACAGTTAATATCACTGCAGGCTTTCCTGTGGTTGGTCAGAAAGATAAG

CCAGTTGATAATGCCAAATGTAGTATCAAAGGAGGCTCTAGGTTTTGTCTATC

ATCTCAGTTCAGAGGCAACGAAACTGGACTCATTACTCCAAATAAACATGGA

CTTTTACAAAACCCATATCGTATACCACCACTTTTTCCCATCAAGTCATTTGTT

AAAACTAAATGTAAGAAAAATCTGCTAGAGGAAAACTTTGAGGAACATTCAA

TGTCACCTGAAAGAGAAATGGGAAATGAGAACATTCCAAGTACAGTGAGCA

CAATTAGCCGTAATAACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTCAAG

CAATATTAATGAAGTAGGTTCCAGTACTAATGAAGTGGGCTCCAGTATTAAT

GAAATAGGTTCCAGTGATGAAAACATTCAAGCAGAACTAGGTAGAAACAGA

GGGCCAAAATTGAATGCTATGCTTAGATTAGGGGTTTTGCAACCTGAGGTCT

ATAAACAAAGTCTTCCTGGAAGTAATTGTAAGCATCCTGAAATAAAAAAGCA

AGAATATGAAGAAGTAGTTCAGACTGTTAATACAGATTTCTCTCCATATCTGA

TTTCAGATAACTTAGAACAGCCTATGGGAAGTAGTCATGCATCTCAGGTTTGT

TCTGAGACACCTGATGACCTGTTAGATGATGGTGAAATAAAGGAAGATACTA

GTTTTGCTGAAAATGACATTAAGGAAAGTTCTGCTGTTTTTAGCAAAAGCGTC

CAGAAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTTCACCCATACACATTTGG

CTCAGGGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAGAAGAGAACTT

ATCTAGTGAGGATGAAGAGCTTCCCTGCTTCCAACACTTGTTATTTGGTAAAG

TAAACAATATACCTTCTCAGTCTACTAGGCATAGCACCGTTGCTACCGAGTGT

CTGTCTAAGAACACAGAGGAGAATTTATTATCATTGAAGAATAGCTTAAATG

ACTGCAGTAACCAGGTAATATTGGCAAAGGCATCTCAGGAACATCACCTTAG

TGAGGAAACAAAATGTTCTGCTAGCTTGTTTTCTTCACAGTGCAGTGAATTGG

AAGACTTGACTGCAAATACAAACACCCAGGATCCTTTCTTGATTGGTTCTTCC

AAACAAATGAGGCATCAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACAAG

GAATTGGTTTCAGATGATGAAGAAAGAGGAACGGGCTTGGAAGAAAATAAT CAAGAAGAGCAAAGCATGGATTCAAACTTAGGTGAAGCAGCATCTGGGTGTG AGAGTGAAACAAGCGTCTCTGAAGACTGCTCAGGGCTATCCTCTCAGAGTGA CATTTTAACCACTCAGCAGAGGGATACCATGCAACATAACCTGATAAAGCTC CAGCAGGAAATGGCTGAACTAGAAGCTGTGTTAGAACAGCATGGGAGCCAG CCTTCTAACAGCTACCCTTCCATCATAAGTGACTCTTCTGCCCTTGAGGACCT GCGAAATCCAGAACAAAGCACATCAGAAAAAGCAGTATTAACTTCACAGAA AAGTAGTGAATACCCTATAAGCCAGAATCCAGAAGGCCTTTCTGCTGACAAG TTTGAGGTGTCTGCAGATAGTTCTACCAGTAAAAATAAAGAACCAGGAGTGG AAAGGTCATCCCCTTCTAAATGCCCATCATTAGATGATAGGTGGTACATGCAC AGTTGCTCTGGGAGTCTTCAGAATAGAAACTACCCATCTCAAGAGGAGCTCA TTAAGGTTGTTGATGTGGAGGAGCAACAGCTGGAAGAGTCTGGGCCACACGA TTTGACGGAAACATCTTACTTGCCAAGGCAAGATCTAGAGGGAACCCCTTAC CTGGAATCTGGAATCAGCCTCTTCTCTGATGACCCTGAATCTGATCCTTCTGA AGACAGAGCCCCAGAGTCAGCTCGTGTTGGCAACATACCATCTTCAACCTCT GCATTGAAAGTTCCCCAATTGAAAGTTGCAGAATCTGCCCAGAGTCCAGCTG CTGCTCATACTACTGATACTGCTGGGTATAATGCAATGGAAGAAAGTGTGAG CAGGGAGAAGCCAGAATTGACAGCTTCAACAGAAAGGGTCAACAAAAGAAT GTCCATGGTGGTGTCTGGCCTGACCCCAGAAGAATTTATGCTCGTGTACAAGT TTGCCAGAAAACACCACATCACTTTAACTAATCTAATTACTGAAGAGACTACT CATGTTGTTATGAAAACAGATGCTGAGTTTGTGTGTGAACGGACACTGAAAT ATTTTCTAGGAATTGCGGGAGGAAAATGGGTAGTTAGCTATTTCTGGGTGAC CCAGTCTATTAAAGAAAGAAAAATGCTGAATGAGCATGATTTTGAAGTCAGA GGAGATGTGGTCAATGGAAGAAACCACCAAGGTCCAAAGCGAGCAAGAGAA TCCCAGGACAGAAAGATCTTCAGGGGGCTAGAAATCTGTTGCTATGGGCCCT TCACCAACATGCCCACAGATCAACTGGAATGGATGGTACAGCTGTGTGGTGC TTCTGTGGTGAAGGAGCTTTCATCATTCACCCTTGGCACAGGTGTCCACCCAA TTGTGGTTGTGCAGCCAGATGCCTGGACAGAGGACAATGGCTTCCATGCAAT TGGGCAGATGTGTGAGGCACCTGTGGTGACCCGAGAGTGGGTGTTGGACAGT GTAGCACTCTACCAGTGCCAGGAGCTGGACACCTACCTGATACCCCAGATCC

CCCACAGCCACTACTGA

Human BRCA1 Protein Sequence, Variant 1 (SEQ ID NO: 15)

MDLSALRVEEVQNVINAMQKILECPICLELIKEPVSTKCDHIFCKFCMLKLLNQK KGPSQCPLCKNDITKRSLQESTRFSQLVEELLKIICAFQLDTGLEYANSYNFAKKE NNSPEHLKDEVSIIQSMGYRNRAKRLLQSEPENPSLQETSLSVQLSNLGTVRTLRT KQRIQPQKTSVYIELGSDSSEDTVNKATYCSVGDQELLQITPQGTRDEISLDSAKK AACEFSETDVTNTEHHQPSNNDLNTTEKRAAERHPEKYQGSSVSNLHVEPCGTN THASSLQHENSSLLLTKDRMNVEKAEFCNKSKQPGLARSQHNRWAGSKETCND RRTPSTEKKVDLNADPLCERKEWNKQKLPCSENPRDTEDVPWITLNSSIQKVNE WFSRSDELLGSDDSHDGESESNAKVADVLDVLNEVDEYSGSSEKIDLLASDPHE ALICKSERVHSKSVESNIEDKIFGKTYRKKASLPNLSHVTENLIIGAFVTEPQIIQER PLTNKLKRKRRPTSGLHPEDFIKKADLAVQKTPEMINQGTNQTEQNGQVMNITN SGHENKTKGDSIQNEKNPNPIESLEKESAFKTKAEPISSSISNMELELNIHNSKAPK KNRLRRKSSTRHIHALELVVSRNLSPPNCTELQIDSCSSSEEIKKKKYNQMPVRHS RNLQLMEGKEPATGAKKSNKPNEQTSKRHDSDTFPELKLTNAPGSFTKCSNTSEL KEFVNPSLPREEKEEKLETVKVSNNAEDPKDLMLSGERVLQTERS VES S SISLVPG TDYGTQESISLLEVSTLGKAKTEPNKCVSQCAAFENPKGLIHGCSKDNRNDTEGF KYPLGHEVNHSRETSIEMEESELDAQYLQNTFKVSKRQSFAPFSNPGNAEEECAT FSAHSGSLKKQSPKVTFECEQKEENQGKNESNIKPVQTVNITAGFPVVGQKDKPV DNAKCSIKGGSRFCLSSQFRGNETGLITPNKHGLLQNPYRIPPLFPIKSFVKTKCKK NLLEENFEEHSMSPEREMGNENIPST VSTISRNNIRENVFKEAS S SNINEVGS STNE VGSSINEIGSSDENIQAELGRNRGPKLNAMLRLGVLQPEVYKQSLPGSNCKHPEIK KQEYEEVVQTVNTDFSPYLISDNLEQPMGSSHASQVCSETPDDLLDDGEIKEDTS FAENDIKESSAVFSKSVQKGELSRSPSPFTHTHLAQGYRRGAKKLESSEENLSSED EELPCFQHLLFGKVNNIPSQSTRHSTVATECLSKNTEENLLSLKNSLNDCSNQVIL AKASQEHHLSEETKCSASLFSSQCSELEDLTANTNTQDPFLIGSSKQMRHQSESQ GVGLSDKELVSDDEERGTGLEENNQEEQSMDSNLGEAASGCESETSVSEDCSGL SSQSDILTTQQRDTMQHNLIKLQQEMAELEAVLEQHGSQPSNSYPSIISDSSALED LRNPEQSTSEKAVLTSQKSSEYPISQNPEGLSADKFEVSADSSTSKNKEPGVERSS PSKCPSLDDRWYMHSCSGSLQNRNYPSQEELIKVVDVEEQQLEESGPHDLTETSY LPRQDLEGTPYLESGISLF SDDPESDPSEDRAPES ARVGNIPS STS ALKVPQLK VAE SAQSPAAAHTTDTAGYNAMEESVSREKPELTASTERVNKRMSMVVSGLTPEEF MLVYKFARKHHITLTNLITEETTHVVMKTDAEFVCERTLKYFLGIAGGKWVVSY FWVTQSIKERKMLNEHDFEVRGDVVNGRNHQGPKRARESQDRKIFRGLEICCYG PFTNMPTDQLEWMVQLCGASVVKELSSFTLGTGVHPIVVVQPDAWTEDNGFHAI GQMCEAPVVTREWVLDSVALYQCQELDTYLIPQIPHSHY

Human BRCA1 cDNA Sequence, Variant 2 (SEQ ID NO: 16)

ATGCTGAAACTTCTCAACCAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTA AGAATGATATAACCAAAAGGAGCCTACAAGAAAGTACGAGATTTAGTCAACT TGTTGAAGAGCTATTGAAAATCATTTGTGCTTTTCAGCTTGACACAGGTTTGG AGTATGCAAACAGCTATAATTTTGCAAAAAAGGAAAATAACTCTCCTGAACA TCTAAAAGATGAAGTTTCTATCATCCAAAGTATGGGCTACAGAAACCGTGCC AAAAGACTTCTACAGAGTGAACCCGAAAATCCTTCCTTGCAGGAAACCAGTC TCAGTGTCCAACTCTCTAACCTTGGAACTGTGAGAACTCTGAGGACAAAGCA GCGGATACAACCTCAAAAGACGTCTGTCTACATTGAATTGGGATCTGATTCTT CTGAAGATACCGTTAATAAGGCAACTTATTGCAGTGTGGGAGATCAAGAATT GTTACAAATCACCCCTCAAGGAACCAGGGATGAAATCAGTTTGGATTCTGCA AAAAAGGCTGCTTGTGAATTTTCTGAGACGGATGTAACAAATACTGAACATC ATCAACCCAGTAATAATGATTTGAACACCACTGAGAAGCGTGCAGCTGAGAG GCATCCAGAAAAGTATCAGGGTAGTTCTGTTTCAAACTTGCATGTGGAGCCA TGTGGCACAAATACTCATGCCAGCTCATTACAGCATGAGAACAGCAGTTTAT TACTCACTAAAGACAGAATGAATGTAGAAAAGGCTGAATTCTGTAATAAAAG CAAACAGCCTGGCTTAGCAAGGAGCCAACATAACAGATGGGCTGGAAGTAA GGAAACATGTAATGATAGGCGGACTCCCAGCACAGAAAAAAAGGTAGATCT GAATGCTGATCCCCTGTGTGAGAGAAAAGAATGGAATAAGCAGAAACTGCC ATGCTCAGAGAATCCTAGAGATACTGAAGATGTTCCTTGGATAACACTAAAT AGCAGCATTCAGAAAGTTAATGAGTGGTTTTCCAGAAGTGATGAACTGTTAG GTTCTGATGACTCACATGATGGGGAGTCTGAATCAAATGCCAAAGTAGCTGA TGTATTGGACGTTCTAAATGAGGTAGATGAATATTCTGGTTCTTCAGAGAAAA TAGACTTACTGGCCAGTGATCCTCATGAGGCTTTAATATGTAAAAGTGAAAG AGTTCACTCCAAATCAGTAGAGAGTAATATTGAAGACAAAATATTTGGGAAA ACCTATCGGAAGAAGGCAAGCCTCCCCAACTTAAGCCATGTAACTGAAAATC TAATTATAGGAGCATTTGTTACTGAGCCACAGATAATACAAGAGCGTCCCCT CACAAATAAATTAAAGCGTAAAAGGAGACCTACATCAGGCCTTCATCCTGAG GATTTTATCAAGAAAGCAGATTTGGCAGTTCAAAAGACTCCTGAAATGATAA ATCAGGGAACTAACCAAACGGAGCAGAATGGTCAAGTGATGAATATTACTAA TAGTGGTCATGAGAATAAAACAAAAGGTGATTCTATTCAGAATGAGAAAAAT CCTAACCCAATAGAATCACTCGAAAAAGAATCTGCTTTCAAAACGAAAGCTG AACCTATAAGCAGCAGTATAAGCAATATGGAACTCGAATTAAATATCCACAA TTCAAAAGCACCTAAAAAGAATAGGCTGAGGAGGAAGTCTTCTACCAGGCAT ATTCATGCGCTTGAACTAGTAGTCAGTAGAAATCTAAGCCCACCTAATTGTAC TGAATTGCAAATTGATAGTTGTTCTAGCAGTGAAGAGATAAAGAAAAAAAAG TACAACCAAATGCCAGTCAGGCACAGCAGAAACCTACAACTCATGGAAGGT AAAGAACCTGCAACTGGAGCCAAGAAGAGTAACAAGCCAAATGAACAGACA AGTAAAAGACATGACAGCGATACTTTCCCAGAGCTGAAGTTAACAAATGCAC CTGGTTCTTTTACTAAGTGTTCAAATACCAGTGAACTTAAAGAATTTGTCAAT CCTAGCCTTCCAAGAGAAGAAAAAGAAGAGAAACTAGAAACAGTTAAAGTG TCTAATAATGCTGAAGACCCCAAAGATCTCATGTTAAGTGGAGAAAGGGTTT TGCAAACTGAAAGATCTGTAGAGAGTAGCAGTATTTCATTGGTACCTGGTAC TGATTATGGCACTCAGGAAAGTATCTCGTTACTGGAAGTTAGCACTCTAGGG AAGGCAAAAACAGAACCAAATAAATGTGTGAGTCAGTGTGCAGCATTTGAA AACCCCAAGGGACTAATTCATGGTTGTTCCAAAGATAATAGAAATGACACAG AAGGCTTTAAGTATCCATTGGGACATGAAGTTAACCACAGTCGGGAAACAAG CATAGAAATGGAAGAAAGTGAACTTGATGCTCAGTATTTGCAGAATACATTC AAGGTTTCAAAGCGCCAGTCATTTGCTCCGTTTTCAAATCCAGGAAATGCAG AAGAGGAATGTGCAACATTCTCTGCCCACTCTGGGTCCTTAAAGAAACAAAG TCCAAAAGTCACTTTTGAATGTGAACAAAAGGAAGAAAATCAAGGAAAGAA TGAGTCTAATATCAAGCCTGTACAGACAGTTAATATCACTGCAGGCTTTCCTG TGGTTGGTCAGAAAGATAAGCCAGTTGATAATGCCAAATGTAGTATCAAAGG AGGCTCTAGGTTTTGTCTATCATCTCAGTTCAGAGGCAACGAAACTGGACTCA TTACTCCAAATAAACATGGACTTTTACAAAACCCATATCGTATACCACCACTT

TTTCCCATCAAGTCATTTGTTAAAACTAAATGTAAGAAAAATCTGCTAGAGG AAAACTTTGAGGAACATTCAATGTCACCTGAAAGAGAAATGGGAAATGAGA ACATTCCAAGTACAGTGAGCACAATTAGCCGTAATAACATTAGAGAAAATGT TTTTAAAGAAGCCAGCTCAAGCAATATTAATGAAGTAGGTTCCAGTACTAAT GAAGTGGGCTCCAGTATTAATGAAATAGGTTCCAGTGATGAAAACATTCAAG CAGAACTAGGTAGAAACAGAGGGCCAAAATTGAATGCTATGCTTAGATTAGG GGTTTTGCAACCTGAGGTCTATAAACAAAGTCTTCCTGGAAGTAATTGTAAGC ATCCTGAAATAAAAAAGCAAGAATATGAAGAAGTAGTTCAGACTGTTAATAC AGATTTCTCTCCATATCTGATTTCAGATAACTTAGAACAGCCTATGGGAAGTA GTCATGCATCTCAGGTTTGTTCTGAGACACCTGATGACCTGTTAGATGATGGT GAAATAAAGGAAGATACTAGTTTTGCTGAAAATGACATTAAGGAAAGTTCTG CTGTTTTTAGCAAAAGCGTCCAGAAAGGAGAGCTTAGCAGGAGTCCTAGCCC

TTTCACCCATACACATTTGGCTCAGGGTTACCGAAGAGGGGCCAAGAAATTA

GAGTCCTCAGAAGAGAACTTATCTAGTGAGGATGAAGAGCTTCCCTGCTTCC

AACACTTGTTATTTGGTAAAGTAAACAATATACCTTCTCAGTCTACTAGGCAT

AGCACCGTTGCTACCGAGTGTCTGTCTAAGAACACAGAGGAGAATTTATTAT

CATTGAAGAATAGCTTAAATGACTGCAGTAACCAGGTAATATTGGCAAAGGC

ATCTCAGGAACATCACCTTAGTGAGGAAACAAAATGTTCTGCTAGCTTGTTTT

CTTCACAGTGCAGTGAATTGGAAGACTTGACTGCAAATACAAACACCCAGGA

TCCTTTCTTGATTGGTTCTTCCAAACAAATGAGGCATCAGTCTGAAAGCCAGG

GAGTTGGTCTGAGTGACAAGGAATTGGTTTCAGATGATGAAGAAAGAGGAAC

GGGCTTGGAAGAAAATAATCAAGAAGAGCAAAGCATGGATTCAAACTTAGG

TGAAGCAGCATCTGGGTGTGAGAGTGAAACAAGCGTCTCTGAAGACTGCTCA

GGGCTATCCTCTCAGAGTGACATTTTAACCACTCAGCAGAGGGATACCATGC

AACATAACCTGATAAAGCTCCAGCAGGAAATGGCTGAACTAGAAGCTGTGTT

AGAACAGCATGGGAGCCAGCCTTCTAACAGCTACCCTTCCATCATAAGTGAC

TCTTCTGCCCTTGAGGACCTGCGAAATCCAGAACAAAGCACATCAGAAAAAG

CAGTATTAACTTCACAGAAAAGTAGTGAATACCCTATAAGCCAGAATCCAGA

AGGCCTTTCTGCTGACAAGTTTGAGGTGTCTGCAGATAGTTCTACCAGTAAAA

ATAAAGAACCAGGAGTGGAAAGGTCATCCCCTTCTAAATGCCCATCATTAGA

TGATAGGTGGTACATGCACAGTTGCTCTGGGAGTCTTCAGAATAGAAACTAC

CCATCTCAAGAGGAGCTCATTAAGGTTGTTGATGTGGAGGAGCAACAGCTGG

AAGAGTCTGGGCCACACGATTTGACGGAAACATCTTACTTGCCAAGGCAAGA

TCTAGAGGGAACCCCTTACCTGGAATCTGGAATCAGCCTCTTCTCTGATGACC

CTGAATCTGATCCTTCTGAAGACAGAGCCCCAGAGTCAGCTCGTGTTGGCAA

CATACCATCTTCAACCTCTGCATTGAAAGTTCCCCAATTGAAAGTTGCAGAAT

CTGCCCAGAGTCCAGCTGCTGCTCATACTACTGATACTGCTGGGTATAATGCA

ATGGAAGAAAGTGTGAGCAGGGAGAAGCCAGAATTGACAGCTTCAACAGAA

AGGGTCAACAAAAGAATGTCCATGGTGGTGTCTGGCCTGACCCCAGAAGAAT

TTATGCTCGTGTACAAGTTTGCCAGAAAACACCACATCACTTTAACTAATCTA

ATTACTGAAGAGACTACTCATGTTGTTATGAAAACAGATGCTGAGTTTGTGTG

TGAACGGACACTGAAATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAGTT

AGCTATTTCTGGGTGACCCAGTCTATTAAAGAAAGAAAAATGCTGAATGAGC

ATGATTTTGAAGTCAGAGGAGATGTGGTCAATGGAAGAAACCACCAAGGTCC

AAAGCGAGCAAGAGAATCCCAGGACAGAAAGATCTTCAGGGGGCTAGAAAT

CTGTTGCTATGGGCCCTTCACCAACATGCCCACAGATCAACTGGAATGGATG

GTACAGCTGTGTGGTGCTTCTGTGGTGAAGGAGCTTTCATCATTCACCCTTGG

CACAGGTGTCCACCCAATTGTGGTTGTGCAGCCAGATGCCTGGACAGAGGAC

AATGGCTTCCATGCAATTGGGCAGATGTGTGAGGCACCTGTGGTGACCCGAG

AGTGGGTGTTGGACAGTGTAGCACTCTACCAGTGCCAGGAGCTGGACACCTA

CCTGATACCCCAGATCCCCCACAGCCACTACTGA

Human BRCA1 Protein Sequence, Variant 2 (SEQ ID NO: 17)

MLKLLNQKKGPSQCPLCKNDITKRSLQESTRFSQLVEELLKIICAFQLDTGLEYAN

SYNFAKKENNSPEHLKDEVSIIQSMGYRNRAKRLLQSEPENPSLQETSLSVQLSNL GTVRTLRTKQRIQPQKTSVYIELGSDSSEDTVNKATYCSVGDQELLQITPQGTRD EISLDSAKKAACEFSETDVTNTEHHQPSNNDLNTTEKRAAERHPEKYQGSSVSNL HVEPCGTNTHAS SLQHENS SLLLTKDRMNVEKAEFCNKSKQPGL ARSQHNRWA GSKETCNDRRTPSTEKKVDLNADPLCERKEWNKQKLPCSENPRDTEDVPWITLN S SIQKVNEWF SRSDELLGSDDSHDGESESNAKVADVLDVLNEVDEYSGS SEKIDL LASDPHEALICKSERVHSKSVESNIEDKIFGKTYRKKASLPNLSHVTENLIIGAFVT EPQIIQERPLTNKLKRKRRPTSGLHPEDFIKKADLAVQKTPEMINQGTNQTEQNG QVMNITNSGHENKTKGDSIQNEKNPNPIESLEKESAFKTKAEPISSSISNMELELNI HNSKAPKKNRLRRKSSTRHIHALELVVSRNLSPPNCTELQIDSCSSSEEIKKKKYN QMPVRHSRNLQLMEGKEPATGAKKSNKPNEQTSKRHDSDTFPELKLTNAPGSFT KCSNTSELKEFVNPSLPREEKEEKLETVKVSNNAEDPKDLMLSGERVLQTERSVE SSSISLVPGTDYGTQESISLLEVSTLGKAKTEPNKCVSQCAAFENPKGLIHGCSKD NRNDTEGFKYPLGHEVNHSRETSIEMEESELDAQYLQNTFKVSKRQSFAPFSNPG NAEEECATFSAHSGSLKKQSPKVTFECEQKEENQGKNESNIKPVQTVNITAGFPV VGQKDKPVDNAKCSIKGGSRFCLSSQFRGNETGLITPNKHGLLQNPYRIPPLFPIK SFVKTKCKKNLLEENFEEHSMSPEREMGNENIPSTVSTISRNNIRENVFKEASSSNI NE VGS STNE VGS SINEIGS SDENIQ AELGRNRGPKLNAMLRLGVLQPEVYKQ SLP GSNCKHPEIKKQEYEEVVQTVNTDFSPYLISDNLEQPMGSSHASQVCSETPDDLL DDGEIKEDTSFAENDIKESSAVFSKSVQKGELSRSPSPFTHTHLAQGYRRGAKKL ESSEENLSSEDEELPCFQHLLFGKVNNIPSQSTRHSTVATECLSKNTEENLLSLKNS LNDCSNQVILAKASQEHHLSEETKCSASLFSSQCSELEDLTANTNTQDPFLIGSSK QMRHQSESQGVGLSDKELVSDDEERGTGLEENNQEEQSMDSNLGEAASGCESET SVSEDCSGLSSQSDILTTQQRDTMQHNLIKLQQEMAELEAVLEQHGSQPSNSYPSI ISDSSALEDLRNPEQSTSEKAVLTSQKSSEYPISQNPEGLSADKFEVSADSSTSKNK EPGVERSSPSKCPSLDDRWYMHSCSGSLQNRNYPSQEELIKVVDVEEQQLEESGP HDLTETSYLPRQDLEGTPYLESGISLFSDDPESDPSEDRAPESARVGNIPSSTSALK VPQLKVAESAQSPAAAHTTDTAGYNAMEESVSREKPELTASTERVNKRMSMVV SGLTPEEFMLVYKFARKHHITLTNLITEETTHVVMKTDAEFVCERTLKYFLGIAG GKWVVSYFWVTQSIKERKMLNEHDFEVRGDVVNGRNHQGPKRARESQDRKIFR GLEICCYGPFTNMPTDQLEWMVQLCGASVVKELSSFTLGTGVHPIVVVQPDAWT

EDNGFHAIGQMCEAPVVTREWVLDSVALYQCQELDTYLIPQIPHSHY

Human BRCA1 cDNA Sequence, Variant 3 (SEQ ID NO: 18)

ATGGATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAATGCTAT GCAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATCAAGGAACCTGTCT CCACAAAGTGTGACCACATATTTTGCAAATTTTGCATGCTGAAACTTCTCAAC CAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGATATAACCAAAA GGAGCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTGAAGAGCTATTGAA AATCATTTGTGCTTTTCAGCTTGACACAGGTTTGGAGTATGCAAACAGCTATA ATTTTGCAAAAAAGGAAAATAACTCTCCTGAACATCTAAAAGATGAAGTTTC TATCATCCAAAGTATGGGCTACAGAAACCGTGCCAAAAGACTTCTACAGAGT GAACCCGAAAATCCTTCCTTGCAGGAAACCAGTCTCAGTGTCCAACTCTCTA ACCTTGGAACTGTGAGAACTCTGAGGACAAAGCAGCGGATACAACCTCAAAA GACGTCTGTCTACATTGAATTGGGATCTGATTCTTCTGAAGATACCGTTAATA AGGCAACTTATTGCAGTGTGGGAGATCAAGAATTGTTACAAATCACCCCTCA AGGAACCAGGGATGAAATCAGTTTGGATTCTGCAAAAAAGGCTGCTTGTGAA TTTTCTGAGACGGATGTAACAAATACTGAACATCATCAACCCAGTAATAATG ATTTGAACACCACTGAGAAGCGTGCAGCTGAGAGGCATCCAGAAAAGTATCA GGGTGAAGCAGCATCTGGGTGTGAGAGTGAAACAAGCGTCTCTGAAGACTGC TCAGGGCTATCCTCTCAGAGTGACATTTTAACCACTCAGCAGAGGGATACCA TGCAACATAACCTGATAAAGCTCCAGCAGGAAATGGCTGAACTAGAAGCTGT GTTAGAACAGCATGGGAGCCAGCCTTCTAACAGCTACCCTTCCATCATAAGT GACTCTTCTGCCCTTGAGGACCTGCGAAATCCAGAACAAAGCACATCAGAAA AAGTATTAACTTCACAGAAAAGTAGTGAATACCCTATAAGCCAGAATCCAGA AGGCCTTTCTGCTGACAAGTTTGAGGTGTCTGCAGATAGTTCTACCAGTAAAA ATAAAGAACCAGGAGTGGAAAGGTCATCCCCTTCTAAATGCCCATCATTAGA TGATAGGTGGTACATGCACAGTTGCTCTGGGAGTCTTCAGAATAGAAACTAC CCATCTCAAGAGGAGCTCATTAAGGTTGTTGATGTGGAGGAGCAACAGCTGG AAGAGTCTGGGCCACACGATTTGACGGAAACATCTTACTTGCCAAGGCAAGA TCTAGAGGGAACCCCTTACCTGGAATCTGGAATCAGCCTCTTCTCTGATGACC CTGAATCTGATCCTTCTGAAGACAGAGCCCCAGAGTCAGCTCGTGTTGGCAA CATACCATCTTCAACCTCTGCATTGAAAGTTCCCCAATTGAAAGTTGCAGAAT CTGCCCAGAGTCCAGCTGCTGCTCATACTACTGATACTGCTGGGTATAATGCA ATGGAAGAAAGTGTGAGCAGGGAGAAGCCAGAATTGACAGCTTCAACAGAA AGGGTCAACAAAAGAATGTCCATGGTGGTGTCTGGCCTGACCCCAGAAGAAT TTATGCTCGTGTACAAGTTTGCCAGAAAACACCACATCACTTTAACTAATCTA ATTACTGAAGAGACTACTCATGTTGTTATGAAAACAGATGCTGAGTTTGTGTG TGAACGGACACTGAAATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAGTT AGCTATTTCTGGGTGACCCAGTCTATTAAAGAAAGAAAAATGCTGAATGAGC

ATGATTTTGAAGTCAGAGGAGATGTGGTCAATGGAAGAAACCACCAAGGTCC AAAGCGAGCAAGAGAATCCCAGGACAGAAAGATCTTCAGGGGGCTAGAAAT CTGTTGCTATGGGCCCTTCACCAACATGCCCACAGATCAACTGGAATGGATG GTACAGCTGTGTGGTGCTTCTGTGGTGAAGGAGCTTTCATCATTCACCCTTGG CACAGGTGTCCACCCAATTGTGGTTGTGCAGCCAGATGCCTGGACAGAGGAC AATGGCTTCCATGCAATTGGGCAGATGTGTGAGGCACCTGTGGTGACCCGAG AGTGGGTGTTGGACAGTGTAGCACTCTACCAGTGCCAGGAGCTGGACACCTA CCTGATACCCCAGATCCCCCACAGCCACTACTGA

Human BRCA1 Protein Sequence, Variant 3 (SEQ ID NO: 19)

MDLSALRVEEVQNVINAMQKILECPICLELIKEPVSTKCDHIFCKFCMLKLLNQK KGPSQCPLCKNDITKRSLQESTRFSQLVEELLKIICAFQLDTGLEYANSYNFAKKE NNSPEHLKDEVSIIQSMGYRNRAKRLLQSEPENPSLQETSLSVQLSNLGTVRTLRT KQRIQPQKTSVYIELGSDSSEDTVNKATYCSVGDQELLQITPQGTRDEISLDSAKK AACEFSETDVTNTEHHQPSNNDLNTTEKRAAERHPEKYQGEAASGCESETSVSE DCSGLSSQSDILTTQQRDTMQHNLIKLQQEMAELEAVLEQHGSQPSNSYPSIISDS SALEDLRNPEQSTSEKVLTSQKSSEYPISQNPEGLSADKFEVSADSSTSKNKEPGV ERSSPSKCPSLDDRWYMHSCSGSLQNRNYPSQEELIKVVDVEEQQLEESGPHDLT ETSYLPRQDLEGTPYLESGISLFSDDPESDPSEDRAPESARVGNIPSSTSALKVPQL KVAESAQSPAAAHTTDTAGYNAMEESVSREKPELTASTERVNKRMSMVVSGLT

PEEFMLVYKFARKHHITLTNLITEETTHVVMKTDAEFVCERTLKYFLGIAGGKW

VVSYFWVTQSIKERKMLNEHDFEVRGDVVNGRNHQGPKRARESQDRKIFRGLEI

CCYGPFTNMPTDQLEWMVQLCGASVVKELSSFTLGTGVHPIVVVQPDAWTEDN

GFHAIGQMCEAPVVTREWVLDSVALYQCQELDTYLIPQIPHSHY

Human BRCA1 cDNA Sequence, Variant 4 (SEQ ID NO: 20)

ATGGATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAATGCTAT

GCAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATCAAGGAACCTGTCT

CCACAAAGTGTGACCACATATTTTGCAAATTTTGCATGCTGAAACTTCTCAAC

CAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGATATAACCAAAA

GGAGCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTGAAGAGCTATTGAA

AATCATTTGTGCTTTTCAGCTTGACACAGGTTTGGAGTATGCAAACAGCTATA

ATTTTGCAAAAAAGGAAAATAACTCTCCTGAACATCTAAAAGATGAAGTTTC

TATCATCCAAAGTATGGGCTACAGAAACCGTGCCAAAAGACTTCTACAGAGT

GAACCCGAAAATCCTTCCTTGCAGGAAACCAGTCTCAGTGTCCAACTCTCTA

ACCTTGGAACTGTGAGAACTCTGAGGACAAAGCAGCGGATACAACCTCAAAA

GACGTCTGTCTACATTGAATTGGGATCTGATTCTTCTGAAGATACCGTTAATA

AGGCAACTTATTGCAGTGTGGGAGATCAAGAATTGTTACAAATCACCCCTCA

AGGAACCAGGGATGAAATCAGTTTGGATTCTGCAAAAAAGGCTGCTTGTGAA

TTTTCTGAGACGGATGTAACAAATACTGAACATCATCAACCCAGTAATAATG

ATTTGAACACCACTGAGAAGCGTGCAGCTGAGAGGCATCCAGAAAAGTATCA

GGGTGAAGCAGCATCTGGGTGTGAGAGTGAAACAAGCGTCTCTGAAGACTGC

TCAGGGCTATCCTCTCAGAGTGACATTTTAACCACTCAGCAGAGGGATACCA

TGCAACATAACCTGATAAAGCTCCAGCAGGAAATGGCTGAACTAGAAGCTGT

GTTAGAACAGCATGGGAGCCAGCCTTCTAACAGCTACCCTTCCATCATAAGT

GACTCTTCTGCCCTTGAGGACCTGCGAAATCCAGAACAAAGCACATCAGAAA

AAGTATTAACTTCACAGAAAAGTAGTGAATACCCTATAAGCCAGAATCCAGA

AGGCCTTTCTGCTGACAAGTTTGAGGTGTCTGCAGATAGTTCTACCAGTAAAA

ATAAAGAACCAGGAGTGGAAAGGTCATCCCCTTCTAAATGCCCATCATTAGA

TGATAGGTGGTACATGCACAGTTGCTCTGGGAGTCTTCAGAATAGAAACTAC

CCATCTCAAGAGGAGCTCATTAAGGTTGTTGATGTGGAGGAGCAACAGCTGG

AAGAGTCTGGGCCACACGATTTGACGGAAACATCTTACTTGCCAAGGCAAGA

TCTAGAGGGAACCCCTTACCTGGAATCTGGAATCAGCCTCTTCTCTGATGACC

CTGAATCTGATCCTTCTGAAGACAGAGCCCCAGAGTCAGCTCGTGTTGGCAA

CATACCATCTTCAACCTCTGCATTGAAAGTTCCCCAATTGAAAGTTGCAGAAT

CTGCCCAGAGTCCAGCTGCTGCTCATACTACTGATACTGCTGGGTATAATGCA

ATGGAAGAAAGTGTGAGCAGGGAGAAGCCAGAATTGACAGCTTCAACAGAA

AGGGTCAACAAAAGAATGTCCATGGTGGTGTCTGGCCTGACCCCAGAAGAAT

TTATGCTCGTGTACAAGTTTGCCAGAAAACACCACATCACTTTAACTAATCTA

ATTACTGAAGAGACTACTCATGTTGTTATGAAAACAGATGCTGAGTTTGTGTG

TGAACGGACACTGAAATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAGTT

AGCTATTTCTGGGTGACCCAGTCTATTAAAGAAAGAAAAATGCTGAATGAGC

ATGATTTTGAAGTCAGAGGAGATGTGGTCAATGGAAGAAACCACCAAGGTCC AAAGCGAGCAAGAGAATCCCAGGACAGAAAGATCTTCAGGGGGCTAGAAAT CTGTTGCTATGGGCCCTTCACCAACATGCCCACAGGGTGTCCACCCAATTGTG GTTGTGCAGCCAGATGCCTGGACAGAGGACAATGGCTTCCATGCAATTGGGC AGATGTGTGA

Human BRCA1 Protein Sequence, Variant 4 (SEQ ID NO: 21)

MDLSALRVEEVQNVINAMQKILECPICLELIKEPVSTKCDHIFCKFCMLKLLNQK KGPSQCPLCKNDITKRSLQESTRFSQLVEELLKIICAFQLDTGLEYANSYNFAKKE NNSPEHLKDEVSIIQSMGYRNRAKRLLQSEPENPSLQETSLSVQLSNLGTVRTLRT KQRIQPQKTSVYIELGSDSSEDTVNKATYCSVGDQELLQITPQGTRDEISLDSAKK

AACEFSETDVTNTEHHQPSNNDLNTTEKRAAERHPEKYQGEAASGCESETSVSE

DCSGLSSQSDILTTQQRDTMQHNLIKLQQEMAELEAVLEQHGSQPSNSYPSIISDS SALEDLRNPEQSTSEKVLTSQKSSEYPISQNPEGLSADKFEVSADSSTSKNKEPGV ERSSPSKCPSLDDRWYMHSCSGSLQNRNYPSQEELIKVVDVEEQQLEESGPHDLT ETSYLPRQDLEGTPYLESGISLFSDDPESDPSEDRAPESARVGNIPSSTSALKVPQL

KVAESAQSPAAAHTTDTAGYNAMEESVSREKPELTASTERVNKRMSMVVSGLT PEEFMLVYKFARKHHITLTNLITEETTHVVMKTDAEFVCERTLKYFLGIAGGKW VVSYFWVTQSIKERKMLNEHDFEVRGDVVNGRNHQGPKRARESQDRKIFRGLEI CCYGPFTNMPTGCPPNCGCAARCLDRGQWLPCNWADV

Human BRCA1 cDNA Sequence, Variant 5 (SEQ ID NO: 22)

ATGGATTTATCTGCTCTTCGCGTTGAAGAAGTACAAAATGTCATTAATGCTAT GCAGAAAATCTTAGAGTGTCCCATCTGTCTGGAGTTGATCAAGGAACCTGTCT CCACAAAGTGTGACCACATATTTTGCAAATTTTGCATGCTGAAACTTCTCAAC CAGAAGAAAGGGCCTTCACAGTGTCCTTTATGTAAGAATGATATAACCAAAA

GGAGCCTACAAGAAAGTACGAGATTTAGTCAACTTGTTGAAGAGCTATTGAA AATCATTTGTGCTTTTCAGCTTGACACAGGTTTGGAGTATGCAAACAGCTATA ATTTTGCAAAAAAGGAAAATAACTCTCCTGAACATCTAAAAGATGAAGTTTC TATCATCCAAAGTATGGGCTACAGAAACCGTGCCAAAAGACTTCTACAGAGT

GAACCCGAAAATCCTTCCTTGCAGGAAACCAGTCTCAGTGTCCAACTCTCTA ACCTTGGAACTGTGAGAACTCTGAGGACAAAGCAGCGGATACAACCTCAAAA GACGTCTGTCTACATTGAATTGGGATCTGATTCTTCTGAAGATACCGTTAATA AGGCAACTTATTGCAGTGTGGGAGATCAAGAATTGTTACAAATCACCCCTCA

AGGAACCAGGGATGAAATCAGTTTGGATTCTGCAAAAAAGGCTGCTTGTGAA TTTTCTGAGACGGATGTAACAAATACTGAACATCATCAACCCAGTAATAATG ATTTGAACACCACTGAGAAGCGTGCAGCTGAGAGGCATCCAGAAAAGTATCA GGGTAGTTCTGTTTCAAACTTGCATGTGGAGCCATGTGGCACAAATACTCATG

CCAGCTCATTACAGCATGAGAACAGCAGTTTATTACTCACTAAAGACAGAAT GAATGTAGAAAAGGCTGAATTCTGTAATAAAAGCAAACAGCCTGGCTTAGCA AGGAGCCAACATAACAGATGGGCTGGAAGTAAGGAAACATGTAATGATAGG CGGACTCCCAGCACAGAAAAAAAGGTAGATCTGAATGCTGATCCCCTGTGTG

AGAGAAAAGAATGGAATAAGCAGAAACTGCCATGCTCAGAGAATCCTAGAG ATACTGAAGATGTTCCTTGGATAACACTAAATAGCAGCATTCAGAAAGTTAA TGAGTGGTTTTCCAGAAGTGATGAACTGTTAGGTTCTGATGACTCACATGATG

GGGAGTCTGAATCAAATGCCAAAGTAGCTGATGTATTGGACGTTCTAAATGA

GGTAGATGAATATTCTGGTTCTTCAGAGAAAATAGACTTACTGGCCAGTGAT

CCTCATGAGGCTTTAATATGTAAAAGTGAAAGAGTTCACTCCAAATCAGTAG

AGAGTAATATTGAAGACAAAATATTTGGGAAAACCTATCGGAAGAAGGCAA

GCCTCCCCAACTTAAGCCATGTAACTGAAAATCTAATTATAGGAGCATTTGTT

ACTGAGCCACAGATAATACAAGAGCGTCCCCTCACAAATAAATTAAAGCGTA

AAAGGAGACCTACATCAGGCCTTCATCCTGAGGATTTTATCAAGAAAGCAGA

TTTGGCAGTTCAAAAGACTCCTGAAATGATAAATCAGGGAACTAACCAAACG

GAGCAGAATGGTCAAGTGATGAATATTACTAATAGTGGTCATGAGAATAAAA

CAAAAGGTGATTCTATTCAGAATGAGAAAAATCCTAACCCAATAGAATCACT

CGAAAAAGAATCTGCTTTCAAAACGAAAGCTGAACCTATAAGCAGCAGTATA

AGCAATATGGAACTCGAATTAAATATCCACAATTCAAAAGCACCTAAAAAGA

ATAGGCTGAGGAGGAAGTCTTCTACCAGGCATATTCATGCGCTTGAACTAGT

AGTCAGTAGAAATCTAAGCCCACCTAATTGTACTGAATTGCAAATTGATAGTT

GTTCTAGCAGTGAAGAGATAAAGAAAAAAAAGTACAACCAAATGCCAGTCA

GGCACAGCAGAAACCTACAACTCATGGAAGGTAAAGAACCTGCAACTGGAG

CCAAGAAGAGTAACAAGCCAAATGAACAGACAAGTAAAAGACATGACAGCG

ATACTTTCCCAGAGCTGAAGTTAACAAATGCACCTGGTTCTTTTACTAAGTGT

TCAAATACCAGTGAACTTAAAGAATTTGTCAATCCTAGCCTTCCAAGAGAAG

AAAAAGAAGAGAAACTAGAAACAGTTAAAGTGTCTAATAATGCTGAAGACC

CCAAAGATCTCATGTTAAGTGGAGAAAGGGTTTTGCAAACTGAAAGATCTGT

AGAGAGTAGCAGTATTTCATTGGTACCTGGTACTGATTATGGCACTCAGGAA

AGTATCTCGTTACTGGAAGTTAGCACTCTAGGGAAGGCAAAAACAGAACCAA

ATAAATGTGTGAGTCAGTGTGCAGCATTTGAAAACCCCAAGGGACTAATTCA

TGGTTGTTCCAAAGATAATAGAAATGACACAGAAGGCTTTAAGTATCCATTG

GGACATGAAGTTAACCACAGTCGGGAAACAAGCATAGAAATGGAAGAAAGT

GAACTTGATGCTCAGTATTTGCAGAATACATTCAAGGTTTCAAAGCGCCAGTC

ATTTGCTCCGTTTTCAAATCCAGGAAATGCAGAAGAGGAATGTGCAACATTC

TCTGCCCACTCTGGGTCCTTAAAGAAACAAAGTCCAAAAGTCACTTTTGAATG

TGAACAAAAGGAAGAAAATCAAGGAAAGAATGAGTCTAATATCAAGCCTGT

ACAGACAGTTAATATCACTGCAGGCTTTCCTGTGGTTGGTCAGAAAGATAAG

CCAGTTGATAATGCCAAATGTAGTATCAAAGGAGGCTCTAGGTTTTGTCTATC

ATCTCAGTTCAGAGGCAACGAAACTGGACTCATTACTCCAAATAAACATGGA

CTTTTACAAAACCCATATCGTATACCACCACTTTTTCCCATCAAGTCATTTGTT

AAAACTAAATGTAAGAAAAATCTGCTAGAGGAAAACTTTGAGGAACATTCAA

TGTCACCTGAAAGAGAAATGGGAAATGAGAACATTCCAAGTACAGTGAGCA

CAATTAGCCGTAATAACATTAGAGAAAATGTTTTTAAAGAAGCCAGCTCAAG

CAATATTAATGAAGTAGGTTCCAGTACTAATGAAGTGGGCTCCAGTATTAAT

GAAATAGGTTCCAGTGATGAAAACATTCAAGCAGAACTAGGTAGAAACAGA

GGGCCAAAATTGAATGCTATGCTTAGATTAGGGGTTTTGCAACCTGAGGTCT

ATAAACAAAGTCTTCCTGGAAGTAATTGTAAGCATCCTGAAATAAAAAAGCA

AGAATATGAAGAAGTAGTTCAGACTGTTAATACAGATTTCTCTCCATATCTGA

TTTCAGATAACTTAGAACAGCCTATGGGAAGTAGTCATGCATCTCAGGTTTGT

TCTGAGACACCTGATGACCTGTTAGATGATGGTGAAATAAAGGAAGATACTA GTTTTGCTGAAAATGACATTAAGGAAAGTTCTGCTGTTTTTAGCAAAAGCGTC

CAGAAAGGAGAGCTTAGCAGGAGTCCTAGCCCTTTCACCCATACACATTTGG

CTCAGGGTTACCGAAGAGGGGCCAAGAAATTAGAGTCCTCAGAAGAGAACTT

ATCTAGTGAGGATGAAGAGCTTCCCTGCTTCCAACACTTGTTATTTGGTAAAG

TAAACAATATACCTTCTCAGTCTACTAGGCATAGCACCGTTGCTACCGAGTGT

CTGTCTAAGAACACAGAGGAGAATTTATTATCATTGAAGAATAGCTTAAATG

ACTGCAGTAACCAGGTAATATTGGCAAAGGCATCTCAGGAACATCACCTTAG

TGAGGAAACAAAATGTTCTGCTAGCTTGTTTTCTTCACAGTGCAGTGAATTGG

AAGACTTGACTGCAAATACAAACACCCAGGATCCTTTCTTGATTGGTTCTTCC

AAACAAATGAGGCATCAGTCTGAAAGCCAGGGAGTTGGTCTGAGTGACAAG

GAATTGGTTTCAGATGATGAAGAAAGAGGAACGGGCTTGGAAGAAAATAAT

CAAGAAGAGCAAAGCATGGATTCAAACTTAGGTGAAGCAGCATCTGGGTGTG

AGAGTGAAACAAGCGTCTCTGAAGACTGCTCAGGGCTATCCTCTCAGAGTGA

CATTTTAACCACTCAGCAGAGGGATACCATGCAACATAACCTGATAAAGCTC

CAGCAGGAAATGGCTGAACTAGAAGCTGTGTTAGAACAGCATGGGAGCCAG

CCTTCTAACAGCTACCCTTCCATCATAAGTGACTCTTCTGCCCTTGAGGACCT

GCGAAATCCAGAACAAAGCACATCAGAAAAAGATTCGCATATACATGGCCA

AAGGAACAACTCCATGTTTTCTAAAAGGCCTAGAGAACATATATCAGTATTA

ACTTCACAGAAAAGTAGTGAATACCCTATAAGCCAGAATCCAGAAGGCCTTT

CTGCTGACAAGTTTGAGGTGTCTGCAGATAGTTCTACCAGTAAAAATAAAGA

ACCAGGAGTGGAAAGGTCATCCCCTTCTAAATGCCCATCATTAGATGATAGG

TGGTACATGCACAGTTGCTCTGGGAGTCTTCAGAATAGAAACTACCCATCTCA

AGAGGAGCTCATTAAGGTTGTTGATGTGGAGGAGCAACAGCTGGAAGAGTCT

GGGCCACACGATTTGACGGAAACATCTTACTTGCCAAGGCAAGATCTAGAGG

GAACCCCTTACCTGGAATCTGGAATCAGCCTCTTCTCTGATGACCCTGAATCT

GATCCTTCTGAAGACAGAGCCCCAGAGTCAGCTCGTGTTGGCAACATACCAT

CTTCAACCTCTGCATTGAAAGTTCCCCAATTGAAAGTTGCAGAATCTGCCCAG

AGTCCAGCTGCTGCTCATACTACTGATACTGCTGGGTATAATGCAATGGAAG

AAAGTGTGAGCAGGGAGAAGCCAGAATTGACAGCTTCAACAGAAAGGGTCA

ACAAAAGAATGTCCATGGTGGTGTCTGGCCTGACCCCAGAAGAATTTATGCT

CGTGTACAAGTTTGCCAGAAAACACCACATCACTTTAACTAATCTAATTACTG

AAGAGACTACTCATGTTGTTATGAAAACAGATGCTGAGTTTGTGTGTGAACG

GACACTGAAATATTTTCTAGGAATTGCGGGAGGAAAATGGGTAGTTAGCTAT

TTCTGGGTGACCCAGTCTATTAAAGAAAGAAAAATGCTGAATGAGCATGATT

TTGAAGTCAGAGGAGATGTGGTCAATGGAAGAAACCACCAAGGTCCAAAGC

GAGCAAGAGAATCCCAGGACAGAAAGATCTTCAGGGGGCTAGAAATCTGTT

GCTATGGGCCCTTCACCAACATGCCCACAGATCAACTGGAATGGATGGTACA

GCTGTGTGGTGCTTCTGTGGTGAAGGAGCTTTCATCATTCACCCTTGGCACAG

GTGTCCACCCAATTGTGGTTGTGCAGCCAGATGCCTGGACAGAGGACAATGG

CTTCCATGCAATTGGGCAGATGTGTGAGGCACCTGTGGTGACCCGAGAGTGG

GTGTTGGACAGTGTAGCACTCTACCAGTGCCAGGAGCTGGACACCTACCTGA

TACCCCAGATCCCCCACAGCCACTACTGA Human BRCA1 Protein Sequence, Variant 5 (SEQ ID NO: 23)

MDLSALRVEEVQNVINAMQKILECPICLELIKEPVSTKCDHIFCKFCMLKLLNQK

KGPSQCPLCKNDITKRSLQESTRFSQLVEELLKIICAFQLDTGLEYANSYNFAKKE

NNSPEHLKDEVSIIQSMGYRNRAKRLLQSEPENPSLQETSLSVQLSNLGTVRTLRT

KQRIQPQKTSVYIELGSDSSEDTVNKATYCSVGDQELLQITPQGTRDEISLDSAKK

AACEFSETDVTNTEHHQPSNNDLNTTEKRAAERHPEKYQGSSVSNLHVEPCGTN

THASSLQHENSSLLLTKDRMNVEKAEFCNKSKQPGLARSQHNRWAGSKETCND

RRTPSTEKKVDLNADPLCERKEWNKQKLPCSENPRDTEDVPWITLNSSIQKVNE

WFSRSDELLGSDDSHDGESESNAKVADVLDVLNEVDEYSGSSEKIDLLASDPHE

ALICKSERVHSKSVESNIEDKIFGKTYRKKASLPNLSHVTENLIIGAFVTEPQIIQE R

PLTNKLKRKRRPTSGLHPEDFIKKADLAVQKTPEMINQGTNQTEQNGQVMNITN

SGHENKTKGDSIQNEKNPNPIESLEKESAFKTKAEPISSSISNMELELNIHNSKAPK

KNRLRRKSSTRHIHALELVVSRNLSPPNCTELQIDSCSSSEEIKKKKYNQMPVRHS

RNLQLMEGKEPATGAKKSNKPNEQTSKRHDSDTFPELKLTNAPGSFTKCSNTSEL

KEFVNPSLPREEKEEKLETVKVSNNAEDPKDLMLSGERVLQTERSVESSSISLVPG

TDYGTQESISLLEVSTLGKAKTEPNKCVSQCAAFENPKGLIHGCSKDNRNDTEGF

KYPLGHEVNHSRETSIEMEESELDAQYLQNTFKVSKRQSFAPFSNPGNAEEECAT

FSAHSGSLKKQSPKVTFECEQKEENQGKNESNIKPVQTVNITAGFPVVGQKDKPV

DNAKCSIKGGSRFCLSSQFRGNETGLITPNKHGLLQNPYRIPPLFPIKSFVKTKCKK

NLLEENFEEHSMSPEREMGNENIPST VSTISRNNIRENVFKEAS S SNINEVGS STNE

VGSSINEIGSSDENIQAELGRNRGPKLNAMLRLGVLQPEVYKQSLPGSNCKHPEIK

KQEYEEVVQTVNTDFSPYLISDNLEQPMGSSHASQVCSETPDDLLDDGEIKEDTS

FAENDIKESSAVFSKSVQKGELSRSPSPFTHTHLAQGYRRGAKKLESSEENLSSED

EELPCFQHLLFGKVNNIPSQSTRHSTVATECLSKNTEENLLSLKNSLNDCSNQVIL

AKASQEHHLSEETKCSASLFSSQCSELEDLTANTNTQDPFLIGSSKQMRHQSESQ

GVGLSDKELVSDDEERGTGLEENNQEEQSMDSNLGEAASGCESETSVSEDCSGL

SSQSDILTTQQRDTMQHNLIKLQQEMAELEAVLEQHGSQPSNSYPSIISDSSALED

LRNPEQSTSEKDSHIHGQRNNSMFSKRPREHISVLTSQKSSEYPISQNPEGLSADK

FEVSADSSTSKNKEPGVERSSPSKCPSLDDRWYMHSCSGSLQNRNYPSQEELIKV

VDVEEQQLEESGPHDLTETSYLPRQDLEGTPYLESGISLFSDDPESDPSEDRAPES

ARVGNIPSSTSALKVPQLKVAESAQSPAAAHTTDTAGYNAMEESVSREKPELTAS

TERVNKRMSMVVSGLTPEEFMLVYKFARKHHITLTNLITEETTHVVMKTDAEFV

CERTLKYFLGIAGGKWVVSYFWVTQSIKERKMLNEHDFEVRGDVVNGRNHQGP

KRARESQDRKIFRGLEICCYGPFTNMPTDQLEWMVQLCGASVVKELSSFTLGTG

VHPIVVVQPDAWTEDNGFHAIGQMCEAPVVTREWVLDSVALYQCQELDTYLIP QIPHSHY

Human BRCA2 cDNA Sequence (SEQ ID NO: 24)

ATGCCTATTGGATCCAAAGAGAGGCCAACATTTTTTGAAATTTTTAAGACACG

CTGCAACAAAGCAGATTTAGGACCAATAAGTCTTAATTGGTTTGAAGAACTT

TCTTCAGAAGCTCCACCCTATAATTCTGAACCTGCAGAAGAATCTGAACATA

AAAACAACAATTACGAACCAAACCTATTTAAAACTCCACAAAGGAAACCATC

TTATAATCAGCTGGCTTCAACTCCAATAATATTCAAAGAGCAAGGGCTGACT CTGCCGCTGTACCAATCTCCTGTAAAAGAATTAGATAAATTCAAATTAGACTT

AGGAAGGAATGTTCCCAATAGTAGACATAAAAGTCTTCGCACAGTGAAAACT

AAAATGGATCAAGCAGATGATGTTTCCTGTCCACTTCTAAATTCTTGTCTTAG

TGAAAGTCCTGTTGTTCTACAATGTACACATGTAACACCACAAAGAGATAAG

TCAGTGGTATGTGGGAGTTTGTTTCATACACCAAAGTTTGTGAAGGGTCGTCA

GACACCAAAACATATTTCTGAAAGTCTAGGAGCTGAGGTGGATCCTGATATG

TCTTGGTCAAGTTCTTTAGCTACACCACCCACCCTTAGTTCTACTGTGCTCATA

GTCAGAAATGAAGAAGCATCTGAAACTGTATTTCCTCATGATACTACTGCTA

ATGTGAAAAGCTATTTTTCCAATCATGATGAAAGTCTGAAGAAAAATGATAG

ATTTATCGCTTCTGTGACAGACAGTGAAAACACAAATCAAAGAGAAGCTGCA

AGTCATGGATTTGGAAAAACATCAGGGAATTCATTTAAAGTAAATAGCTGCA

AAGACCACATTGGAAAGTCAATGCCAAATGTCCTAGAAGATGAAGTATATGA

AACAGTTGTAGATACCTCTGAAGAAGATAGTTTTTCATTATGTTTTTCTAAAT

GTAGAACAAAAAATCTACAAAAAGTAAGAACTAGCAAGACTAGGAAAAAAA

TTTTCCATGAAGCAAACGCTGATGAATGTGAAAAATCTAAAAACCAAGTGAA

AGAAAAATACTCATTTGTATCTGAAGTGGAACCAAATGATACTGATCCATTA

GATTCAAATGTAGCAAATCAGAAGCCCTTTGAGAGTGGAAGTGACAAAATCT

CCAAGGAAGTTGTACCGTCTTTGGCCTGTGAATGGTCTCAACTAACCCTTTCA GGTCTAAATGGAGCCCAGATGGAGAAAATACCCCTATTGCATATTTCTTCATG TGACCAAAATATTTCAGAAAAAGACCTATTAGACACAGAGAACAAAAGAAA GAAAGATTTTCTTACTTCAGAGAATTCTTTGCCACGTATTTCTAGCCTACCAA

AATCAGAGAAGCCATTAAATGAGGAAACAGTGGTAAATAAGAGAGATGAAG

AGCAGCATCTTGAATCTCATACAGACTGCATTCTTGCAGTAAAGCAGGCAAT

ATCTGGAACTTCTCCAGTGGCTTCTTCATTTCAGGGTATCAAAAAGTCTATAT

TCAGAATAAGAGAATCACCTAAAGAGACTTTCAATGCAAGTTTTTCAGGTCA

TATGACTGATCCAAACTTTAAAAAAGAAACTGAAGCCTCTGAAAGTGGACTG

GAAATACATACTGTTTGCTCACAGAAGGAGGACTCCTTATGTCCAAATTTAAT

TGATAATGGAAGCTGGCCAGCCACCACCACACAGAATTCTGTAGCTTTGAAG

AATGCAGGTTTAATATCCACTTTGAAAAAGAAAACAAATAAGTTTATTTATG

CTATACATGATGAAACATCTTATAAAGGAAAAAAAATACCGAAAGACCAAA

AATCAGAACTAATTAACTGTTCAGCCCAGTTTGAAGCAAATGCTTTTGAAGC

ACCACTTACATTTGCAAATGCTGATTCAGGTTTATTGCATTCTTCTGTGAAAA GAAGCTGTTCACAGAATGATTCTGAAGAACCAACTTTGTCCTTAACTAGCTCT TTTGGGACAATTCTGAGGAAATGTTCTAGAAATGAAACATGTTCTAATAATA

CAGTAATCTCTCAGGATCTTGATTATAAAGAAGCAAAATGTAATAAGGAAAA

ACTACAGTTATTTATTACCCCAGAAGCTGATTCTCTGTCATGCCTGCAGGAAG

GACAGTGTGAAAATGATCCAAAAAGCAAAAAAGTTTCAGATATAAAAGAAG

AGGTCTTGGCTGCAGCATGTCACCCAGTACAACATTCAAAAGTGGAATACAG

TGATACTGACTTTCAATCCCAGAAAAGTCTTTTATATGATCATGAAAATGCCA

GCACTCTTATTTTAACTCCTACTTCCAAGGATGTTCTGTCAAACCTAGTCATG

ATTTCTAGAGGCAAAGAATCATACAAAATGTCAGACAAGCTCAAAGGTAACA

ATTATGAATCTGATGTTGAATTAACCAAAAATATTCCCATGGAAAAGAATCA

AGATGTATGTGCTTTAAATGAAAATTATAAAAACGTTGAGCTGTTGCCACCTG AAAAATACATGAGAGTAGCATCACCTTCAAGAAAGGTACAATTCAACCAAAA CACAAATCTAAGAGTAATCCAAAAAAATCAAGAAGAAACTACTTCAATTTCA AAAATAACTGTCAATCCAGACTCTGAAGAACTTTTCTCAGACAATGAGAATA

ATTTTGTCTTCCAAGTAGCTAATGAAAGGAATAATCTTGCTTTAGGAAATACT

AAGGAACTTCATGAAACAGACTTGACTTGTGTAAACGAACCCATTTTCAAGA

ACTCTACCATGGTTTTATATGGAGACACAGGTGATAAACAAGCAACCCAAGT

GTCAATTAAAAAAGATTTGGTTTATGTTCTTGCAGAGGAGAACAAAAATAGT

GTAAAGCAGCATATAAAAATGACTCTAGGTCAAGATTTAAAATCGGACATCT

CCTTGAATATAGATAAAATACCAGAAAAAAATAATGATTACATGAACAAATG

GGCAGGACTCTTAGGTCCAATTTCAAATCACAGTTTTGGAGGTAGCTTCAGA

ACAGCTTCAAATAAGGAAATCAAGCTCTCTGAACATAACATTAAGAAGAGCA

AAATGTTCTTCAAAGATATTGAAGAACAATATCCTACTAGTTTAGCTTGTGTT

GAAATTGTAAATACCTTGGCATTAGATAATCAAAAGAAACTGAGCAAGCCTC

AGTCAATTAATACTGTATCTGCACATTTACAGAGTAGTGTAGTTGTTTCTGAT

TGTAAAAATAGTCATATAACCCCTCAGATGTTATTTTCCAAGCAGGATTTTAA

TTCAAACCATAATTTAACACCTAGCCAAAAGGCAGAAATTACAGAACTTTCT

ACTATATTAGAAGAATCAGGAAGTCAGTTTGAATTTACTCAGTTTAGAAAAC

CAAGCTACATATTGCAGAAGAGTACATTTGAAGTGCCTGAAAACCAGATGAC

TATCTTAAAGACCACTTCTGAGGAATGCAGAGATGCTGATCTTCATGTCATAA

TGAATGCCCCATCGATTGGTCAGGTAGACAGCAGCAAGCAATTTGAAGGTAC

AGTTGAAATTAAACGGAAGTTTGCTGGCCTGTTGAAAAATGACTGTAACAAA

AGTGCTTCTGGTTATTTAACAGATGAAAATGAAGTGGGGTTTAGGGGCTTTTA

TTCTGCTCATGGCACAAAACTGAATGTTTCTACTGAAGCTCTGCAAAAAGCTG

TGAAACTGTTTAGTGATATTGAGAATATTAGTGAGGAAACTTCTGCAGAGGT

ACATCCAATAAGTTTATCTTCAAGTAAATGTCATGATTCTGTTGTTTCAATGTT

TAAGATAGAAAATCATAATGATAAAACTGTAAGTGAAAAAAATAATAAATG

CCAACTGATATTACAAAATAATATTGAAATGACTACTGGCACTTTTGTTGAAG

AAATTACTGAAAATTACAAGAGAAATACTGAAAATGAAGATAACAAATATA

CTGCTGCCAGTAGAAATTCTCATAACTTAGAATTTGATGGCAGTGATTCAAGT

AAAAATGATACTGTTTGTATTCATAAAGATGAAACGGACTTGCTATTTACTGA

TCAGCACAACATATGTCTTAAATTATCTGGCCAGTTTATGAAGGAGGGAAAC

ACTCAGATTAAAGAAGATTTGTCAGATTTAACTTTTTTGGAAGTTGCGAAAGC

TCAAGAAGCATGTCATGGTAATACTTCAAATAAAGAACAGTTAACTGCTACT

AAAACGGAGCAAAATATAAAAGATTTTGAGACTTCTGATACATTTTTTCAGA

CTGCAAGTGGGAAAAATATTAGTGTCGCCAAAGAGTCATTTAATAAAATTGT

AAATTTCTTTGATCAGAAACCAGAAGAATTGCATAACTTTTCCTTAAATTCTG

AATTACATTCTGACATAAGAAAGAACAAAATGGACATTCTAAGTTATGAGGA

AACAGACATAGTTAAACACAAAATACTGAAAGAAAGTGTCCCAGTTGGTACT

GGAAATCAACTAGTGACCTTCCAGGGACAACCCGAACGTGATGAAAAGATCA

AAGAACCTACTCTATTGGGTTTTCATACAGCTAGCGGGAAAAAAGTTAAAAT

TGCAAAGGAATCTTTGGACAAAGTGAAAAACCTTTTTGATGAAAAAGAGCAA

GGTACTAGTGAAATCACCAGTTTTAGCCATCAATGGGCAAAGACCCTAAAGT

ACAGAGAGGCCTGTAAAGACCTTGAATTAGCATGTGAGACCATTGAGATCAC

AGCTGCCCCAAAGTGTAAAGAAATGCAGAATTCTCTCAATAATGATAAAAAC

CTTGTTTCTATTGAGACTGTGGTGCCACCTAAGCTCTTAAGTGATAATTTATG

TAGACAAACTGAAAATCTCAAAACATCAAAAAGTATCTTTTTGAAAGTTAAA

GTACATGAAAATGTAGAAAAAGAAACAGCAAAAAGTCCTGCAACTTGTTACA CAAATCAGTCCCCTTATTCAGTCATTGAAAATTCAGCCTTAGCTTTTTACACA

AGTTGTAGTAGAAAAACTTCTGTGAGTCAGACTTCATTACTTGAAGCAAAAA

AATGGCTTAGAGAAGGAATATTTGATGGTCAACCAGAAAGAATAAATACTGC

AGATTATGTAGGAAATTATTTGTATGAAAATAATTCAAACAGTACTATAGCT

GAAAATGACAAAAATCATCTCTCCGAAAAACAAGATACTTATTTAAGTAACA

GTAGCATGTCTAACAGCTATTCCTACCATTCTGATGAGGTATATAATGATTCA

GGATATCTCTCAAAAAATAAACTTGATTCTGGTATTGAGCCAGTATTGAAGA

ATGTTGAAGATCAAAAAAACACTAGTTTTTCCAAAGTAATATCCAATGTAAA

AGATGCAAATGCATACCCACAAACTGTAAATGAAGATATTTGCGTTGAGGAA

CTTGTGACTAGCTCTTCACCCTGCAAAAATAAAAATGCAGCCATTAAATTGTC

CATATCTAATAGTAATAATTTTGAGGTAGGGCCACCTGCATTTAGGATAGCCA

GTGGTAAAATCGTTTGTGTTTCACATGAAACAATTAAAAAAGTGAAAGACAT

ATTTACAGACAGTTTCAGTAAAGTAATTAAGGAAAACAACGAGAATAAATCA

AAAATTTGCCAAACGAAAATTATGGCAGGTTGTTACGAGGCATTGGATGATT

CAGAGGATATTCTTCATAACTCTCTAGATAATGATGAATGTAGCACGCATTCA

CATAAGGTTTTTGCTGACATTCAGAGTGAAGAAATTTTACAACATAACCAAA

ATATGTCTGGATTGGAGAAAGTTTCTAAAATATCACCTTGTGATGTTAGTTTG

GAAACTTCAGATATATGTAAATGTAGTATAGGGAAGCTTCATAAGTCAGTCT

CATCTGCAAATACTTGTGGGATTTTTAGCACAGCAAGTGGAAAATCTGTCCA

GGTATCAGATGCTTCATTACAAAACGCAAGACAAGTGTTTTCTGAAATAGAA

GATAGTACCAAGCAAGTCTTTTCCAAAGTATTGTTTAAAAGTAACGAACATTC

AGACCAGCTCACAAGAGAAGAAAATACTGCTATACGTACTCCAGAACATTTA

ATATCCCAAAAAGGCTTTTCATATAATGTGGTAAATTCATCTGCTTTCTCTGG

ATTTAGTACAGCAAGTGGAAAGCAAGTTTCCATTTTAGAAAGTTCCTTACACA

AAGTTAAGGGAGTGTTAGAGGAATTTGATTTAATCAGAACTGAGCATAGTCT

TCACTATTCACCTACGTCTAGACAAAATGTATCAAAAATACTTCCTCGTGTTG

ATAAGAGAAACCCAGAGCACTGTGTAAACTCAGAAATGGAAAAAACCTGCA

GTAAAGAATTTAAATTATCAAATAACTTAAATGTTGAAGGTGGTTCTTCAGA

AAATAATCACTCTATTAAAGTTTCTCCATATCTCTCTCAATTTCAACAAGACA

AACAACAGTTGGTATTAGGAACCAAAGTGTCACTTGTTGAGAACATTCATGT

TTTGGGAAAAGAACAGGCTTCACCTAAAAACGTAAAAATGGAAATTGGTAAA

ACTGAAACTTTTTCTGATGTTCCTGTGAAAACAAATATAGAAGTTTGTTCTAC

TTACTCCAAAGATTCAGAAAACTACTTTGAAACAGAAGCAGTAGAAATTGCT

AAAGCTTTTATGGAAGATGATGAACTGACAGATTCTAAACTGCCAAGTCATG

CCACACATTCTCTTTTTACATGTCCCGAAAATGAGGAAATGGTTTTGTCAAAT

TCAAGAATTGGAAAAAGAAGAGGAGAGCCCCTTATCTTAGTGGGAGAACCCT

CAATCAAAAGAAACTTATTAAATGAATTTGACAGGATAATAGAAAATCAAGA

AAAATCCTTAAAGGCTTCAAAAAGCACTCCAGATGGCACAATAAAAGATCGA

AGATTGTTTATGCATCATGTTTCTTTAGAGCCGATTACCTGTGTACCCTTTCGC

ACAACTAAGGAACGTCAAGAGATACAGAATCCAAATTTTACCGCACCTGGTC

AAGAATTTCTGTCTAAATCTCATTTGTATGAACATCTGACTTTGGAAAAATCT

TCAAGCAATTTAGCAGTTTCAGGACATCCATTTTATCAAGTTTCTGCTACAAG

AAATGAAAAAATGAGACACTTGATTACTACAGGCAGACCAACCAAAGTCTTT

GTTCCACCTTTTAAAACTAAATCACATTTTCACAGAGTTGAACAGTGTGTTAG

GAATATTAACTTGGAGGAAAACAGACAAAAGCAAAACATTGATGGACATGG CTCTGATGATAGTAAAAATAAGATTAATGACAATGAGATTCATCAGTTTAAC

AAAAACAACTCCAATCAAGCAGTAGCTGTAACTTTCACAAAGTGTGAAGAAG

AACCTTTAGATTTAATTACAAGTCTTCAGAATGCCAGAGATATACAGGATAT

GCGAATTAAGAAGAAACAAAGGCAACGCGTCTTTCCACAGCCAGGCAGTCTG

TATCTTGCAAAAACATCCACTCTGCCTCGAATCTCTCTGAAAGCAGCAGTAGG

AGGCCAAGTTCCCTCTGCGTGTTCTCATAAACAGCTGTATACGTATGGCGTTT

CTAAACATTGCATAAAAATTAACAGCAAAAATGCAGAGTCTTTTCAGTTTCA

CACTGAAGATTATTTTGGTAAGGAAAGTTTATGGACTGGAAAAGGAATACAG

TTGGCTGATGGTGGATGGCTCATACCCTCCAATGATGGAAAGGCTGGAAAAG

AAGAATTTTATAGGGCTCTGTGTGACACTCCAGGTGTGGATCCAAAGCTTATT

TCTAGAATTTGGGTTTATAATCACTATAGATGGATCATATGGAAACTGGCAGC

TATGGAATGTGCCTTTCCTAAGGAATTTGCTAATAGATGCCTAAGCCCAGAA

AGGGTGCTTCTTCAACTAAAATACAGATATGATACGGAAATTGATAGAAGCA

GAAGATCGGCTATAAAAAAGATAATGGAAAGGGATGACACAGCTGCAAAAA

CACTTGTTCTCTGTGTTTCTGACATAATTTCATTGAGCGCAAATATATCTGAA

ACTTCTAGCAATAAAACTAGTAGTGCAGATACCCAAAAAGTGGCCATTATTG

AACTTACAGATGGGTGGTATGCTGTTAAGGCCCAGTTAGATCCTCCCCTCTTA

GCTGTCTTAAAGAATGGCAGACTGACAGTTGGTCAGAAGATTATTCTTCATG

GAGCAGAACTGGTGGGCTCTCCTGATGCCTGTACACCTCTTGAAGCCCCAGA

ATCTCTTATGTTAAAGATTTCTGCTAACAGTACTCGGCCTGCTCGCTGGTATA

CCAAACTTGGATTCTTTCCTGACCCTAGACCTTTTCCTCTGCCCTTATCATCGC

TTTTCAGTGATGGAGGAAATGTTGGTTGTGTTGATGTAATTATTCAAAGAGCA

TACCCTATACAGTGGATGGAGAAGACATCATCTGGATTATACATATTTCGCA

ATGAAAGAGAGGAAGAAAAGGAAGCAGCAAAATATGTGGAGGCCCAACAA

AAGAGACTAGAAGCCTTATTCACTAAAATTCAGGAGGAATTTGAAGAACATG

AAGAAAACACAACAAAACCATATTTACCATCACGTGCACTAACAAGACAGC

AAGTTCGTGCTTTGCAAGATGGTGCAGAGCTTTATGAAGCAGTGAAGAATGC

AGCAGACCCAGCTTACCTTGAGGGTTATTTCAGTGAAGAGCAGTTAAGAGCC

TTGAATAATCACAGGCAAATGTTGAATGATAAGAAACAAGCTCAGATCCAGT

TGGAAATTAGGAAGGCCATGGAATCTGCTGAACAAAAGGAACAAGGTTTATC

AAGGGATGTCACAACCGTGTGGAAGTTGCGTATTGTAAGCTATTCAAAAAAA

GAAAAAGATTCAGTTATACTGAGTATTTGGCGTCCATCATCAGATTTATATTC

TCTGTTAACAGAAGGAAAGAGATACAGAATTTATCATCTTGCAACTTCAAAA

TCTAAAAGTAAATCTGAAAGAGCTAACATACAGTTAGCAGCGACAAAAAAA

ACTCAGTATCAACAACTACCGGTTTCAGATGAAATTTTATTTCAGATTTACCA

GCCACGGGAGCCCCTTCACTTCAGCAAATTTTTAGATCCAGACTTTCAGCCAT

CTTGTTCTGAGGTGGACCTAATAGGATTTGTCGTTTCTGTTGTGAAAAAAACA

GGACTTGCCCCTTTCGTCTATTTGTCAGACGAATGTTACAATTTACTGGCAAT

AAAGTTTTGGATAGACCTTAATGAGGACATTATTAAGCCTCATATGTTAATTG

CTGCAAGCAACCTCCAGTGGCGACCAGAATCCAAATCAGGCCTTCTTACTTT

ATTTGCTGGAGATTTTTCTGTGTTTTCTGCTAGTCCAAAAGAGGGCCACTTTC

AAGAGACATTCAACAAAATGAAAAATACTGTTGAGAATATTGACATACTTTG

CAATGAAGCAGAAAACAAGCTTATGCATATACTGCATGCAAATGATCCCAAG

TGGTCCACCCCAACTAAAGACTGTACTTCAGGGCCGTACACTGCTCAAATCA

TTCCTGGTACAGGAAACAAGCTTCTGATGTCTTCTCCTAATTGTGAGATATAT TATCAAAGTCCTTTATCACTTTGTATGGCCAAAAGGAAGTCTGTTTCCACACC TGTCTCAGCCCAGATGACTTCAAAGTCTTGTAAAGGGGAGAAAGAGATTGAT GACCAAAAGAACTGCAAAAAGAGAAGAGCCTTGGATTTCTTGAGTAGACTGC CTTTACCTCCACCTGTTAGTCCCATTTGTACATTTGTTTCTCCGGCTGCACAGA AGGCATTTCAGCCACCAAGGAGTTGTGGCACCAAATACGAAACACCCATAAA GAAAAAAGAACTGAATTCTCCTCAGATGACTCCATTTAAAAAATTCAATGAA

ATTTCTCTTTTGGAAAGTAATTCAATAGCTGACGAAGAACTTGCATTGATAAA TACCCAAGCTCTTTTGTCTGGTTCAACAGGAGAAAAACAATTTATATCTGTCA GTGAATCCACTAGGACTGCTCCCACCAGTTCAGAAGATTATCTCAGACTGAA ACGACGTTGTACTACATCTCTGATCAAAGAACAGGAGAGTTCCCAGGCCAGT ACGGAAGAATGTGAGAAAAATAAGCAGGACACAATTACAACTAAAAAATAT ATCTAA

Human BRCA2 Protein Sequence (SEQ ID NO: 25)

MPIGSKERPTFFEIFKTRCNKADLGPISLNWFEELSSEAPPYNSEPAEESEHKNNN YEPNLFKTPQRKPSYNQLASTPIIFKEQGLTLPLYQSPVKELDKFKLDLGRNVPNS RHKSLRTVKTKMDQADDVSCPLLNSCLSESPVVLQCTHVTPQRDKSVVCGSLFH TPKFVKGRQTPKHISESLGAEVDPDMSWSSSLATPPTLSSTVLIVRNEEASETVFP HDTTANVKSYFSNHDESLKKNDRFIASVTDSENTNQREAASHGFGKTSGNSFKV NSCKDHIGKSMPNVLEDEVYETVVDTSEEDSFSLCFSKCRTKNLQKVRTSKTRK

KIFHEANADECEKSKNQVKEKYSFVSEVEPNDTDPLDSNVANQKPFESGSDKISK EVVPSLACEWSQLTLSGLNGAQMEKIPLLHISSCDQNISEKDLLDTENKRKKDFL TSENSLPRISSLPKSEKPLNEETVVNKRDEEQHLESHTDCILAVKQAISGTSPVASS FQGIKKSIFRIRESPKETFNASFSGHMTDPNFKKETEASESGLEIHTVCSQKEDSLC PNLIDNGSWPATTTQNSVALKNAGLISTLKKKTNKFIYAIHDETSYKGKKIPKDQ KSELINCSAQFEANAFEAPLTFANADSGLLHSSVKRSCSQNDSEEPTLSLTSSFGTI

LRKCSRNETCSNNTVISQDLDYKEAKCNKEKLQLFITPEADSLSCLQEGQCENDP KSKKVSDIKEEVLAAACHPVQHSKVEYSDTDFQSQKSLLYDHENASTLILTPTSK DVLSNLVMISRGKESYKMSDKLKGNNYESDVELTKNIPMEKNQDVCALNENYK NVELLPPEKYMRVASPSRKVQFNQNTNLRVIQKNQEETTSISKITVNPDSEELFSD NENNFVFQVANERNNLALGNTKELHETDLTCVNEPIFKNSTMVLYGDTGDKQA TQVSIKKDLVYVLAEENKNSVKQHIKMTLGQDLKSDISLNIDKIPEKNNDYMNK

WAGLLGPISNHSFGGSFRTASNKEIKLSEHNIKKSKMFFKDIEEQYPTSLACVEIV NTLALDNQKKLSKPQSINTVSAHLQSSVVVSDCKNSHITPQMLFSKQDFNSNHNL TPSQKAEITELSTILEESGSQFEFTQFRKPSYILQKSTFEVPENQMTILKTTSEECRD ADLHVIMNAPSIGQVDSSKQFEGTVEIKRKFAGLLKNDCNKSASGYLTDENEVG FRGFYSAHGTKLNVSTEALQKAVKLFSDIENISEETSAEVHPISLSSSKCHDSVVS MFKIENHNDKTVSEKNNKCQLILQNNIEMTTGTFVEEITENYKRNTENEDNKYTA

ASRNSHNLEFDGSDSSKNDTVCIHKDETDLLFTDQHNICLKLSGQFMKEGNTQIK EDLSDLTFLEVAKAQEACHGNTSNKEQLTATKTEQNIKDFETSDTFFQTASGKNI SVAKESFNKIVNFFDQKPEELHNFSLNSELHSDIRKNKMDILSYEETDIVKHKILK ESVPVGTGNQLVTFQGQPERDEKIKEPTLLGFHTASGKKVKIAKESLDKVKNLFD EKEQGTSEITSFSHQWAKTLKYREACKDLELACETIEITAAPKCKEMQNSLNNDK NLVSIETVVPPKLLSDNLCRQTENLKTSKSIFLKVKVHENVEKETAKSPATCYTN QSPYSVIENSALAFYTSCSRKTSVSQTSLLEAKKWLREGIFDGQPERINTADYVGN YLYENNSNSTIAENDKNHLSEKQDTYLSNSSMSNSYSYHSDEVYNDSGYLSKNK LDSGIEPVLKNVEDQKNTSFSKVISNVKDANAYPQTVNEDICVEELVTSSSPCKN KNAAIKLSISNSNNFEVGPPAFRIASGKIVCVSHETIKKVKDIFTDSFSKVIKENNE NKSKICQTKIMAGCYEALDDSEDILHNSLDNDECSTHSHKVFADIQSEEILQHNQ NMSGLEKVSKISPCDVSLETSDICKCSIGKLHKSVSSANTCGIFSTASGKSVQVSD ASLQNARQVFSEIEDSTKQVFSKVLFKSNEHSDQLTREENTAIRTPEHLISQKGFS YNVVNS S AF SGF ST ASGKQ VSILES SLHKVKGVLEEFDLIRTEHSLHYSPTSRQNV SKILPRVDKRNPEHCVNSEMEKTCSKEFKLSNNLNVEGGSSENNHSIKVSPYLSQ FQQDKQQLVLGTKVSLVENIHVLGKEQASPKNVKMEIGKTETFSDVPVKTNIEV CSTYSKDSENYFETEAVEIAKAFMEDDELTDSKLPSHATHSLFTCPENEEMVLSN SRIGKRRGEPLILVGEPSIKRNLLNEFDRIIENQEKSLKASKSTPDGTIKDRRLFMH HVSLEPITCVPFRTTKERQEIQNPNFT APGQEFLSKSHLYEHLTLEKS S SNLAVSG HPFYQVSATRNEKMRHLITTGRPTKVFVPPFKTKSHFHRVEQCVRNINLEENRQK QNIDGHGSDDSKNKINDNEIHQFNKNNSNQAVAVTFTKCEEEPLDLITSLQNARD IQDMRIKKKQRQRVFPQPGSLYLAKTSTLPRISLKAAVGGQVPSACSHKQLYTYG VSKHCIKINSKNAESFQFHTEDYFGKESLWTGKGIQLADGGWLIPSNDGKAGKEE FYRALCDTPGVDPKLISRIWVYNHYRWIIWKLAAMECAFPKEFANRCLSPERVLL QLKYRYDTEIDRSRRS AIKKIMERDDT AAKTLVLC VSDIISLS ANISETS SNKTS S A DTQKVAIIELTDGWYAVKAQLDPPLLAVLKNGRLTVGQKIILHGAELVGSPDAC TPLEAPESLMLKIS ANSTRP ARW YTKLGFFPDPRPFPLPLS SLF SDGGNVGC VD VII QRAYPIQWMEKTSSGLYIFRNEREEEKEAAKYVEAQQKRLEALFTKIQEEFEEHE ENTTKPYLPSRALTRQQVRALQDGAELYEAVKNAADPAYLEGYFSEEQLRALNN HRQMLNDKKQAQIQLEIRKAMESAEQKEQGLSRDVTTVWKLRIVSYSKKEKDS VILSIWRPSSDLYSLLTEGKRYRIYHLATSKSKSKSERANIQLAATKKTQYQQLPV SDEILFQIYQPREPLHFSKFLDPDFQPSCSEVDLIGFVVSVVKKTGLAPFVYLSDEC YNLLAIKFWIDLNEDIIKPHMLIAASNLQWRPESKSGLLTLFAGDFSVFSASPKEG HFQETFNKMKNTVENIDILCNEAENKLMHILHANDPKWSTPTKDCTSGPYTAQII PGTGNKLLMSSPNCEIYYQSPLSLCMAKRKSVSTPVSAQMTSKSCKGEKEIDDQK NCKKRRALDFLSRLPLPPPVSPICTFVSPAAQKAFQPPRSCGTKYETPIKKKELNSP QMTPFKKFNEISLLESNSIADEELALINTQALLSGSTGEKQFISVSESTRTAPTSSED YLRLKRRCTTSLIKEQESSQASTEECEKNKQDTITTKKYI

Human SAMHD1 cDNA Sequence, Variant 1 (SEQ ID NO: 26)

ATGCAGCGAGCCGATTCCGAGCAGCCCTCCAAGCGTCCCCGTTGCGATGACA GCCCGAGAACCCCCTCAAACACCCCTTCCGCAGAGGCAGACTGGTCCCCGGG CCTGGAACTCCATCCCGACTACAAGACATGGGGTCCGGAGCAGGTGTGCTCC TTCCTCAGGCGCGGTGGCTTTGAAGAGCCGGTGCTGCTGAAGAACATCCGAG AAAATGAAATCACAGGCGCATTACTGCCTTGTCTTGATGAGTCTCGTTTTGAA AATCTTGGAGTAAGTTCCTTGGGGGAGAGGAAGAAGCTGCTTAGTTATATCC AGCGATTGGTTCAAATCCACGTTGATACAATGAAGGTAATTAATGATCCTATC CATGGCCACATTGAGCTCCACCCTCTCCTCGTCCGAATCATTGATACACCTCA ATTTCAACGTCTTCGATACATCAAACAGCTGGGAGGTGGTTACTATGTTTTTC CAGGAGCTTCACACAATCGATTTGAGCATAGTCTAGGGGTGGGGTATCTAGC AGGATGTCTAGTTCACGCACTGGGTGAAAAACAACCAGAGCTGCAGATAAGT

GAACGAGATGTTCTCTGTGTTCAGATTGCTGGACTTTGTCATGATCTCGGTCA

TGGGCCATTTTCTCACATGTTTGATGGACGATTTATTCCACTTGCTCGCCCGG

AGGTGAAATGGACGCATGAACAAGGCTCAGTTATGATGTTTGAGCACCTTAT

TAATTCTAATGGAATTAAGCCTGTCATGGAACAATATGGTCTCATCCCTGAAG

AAGATATTTGCTTTATAAAGGAACAAATTGTAGGACCACTTGAATCACCTGTC

GAAGATTCATTGTGGCCATATAAAGGGCGTCCTGAAAACAAAAGCTTCCTTT

ATGAGATAGTATCTAATAAAAGAAATGGCATTGATGTGGACAAATGGGATTA

TTTTGCCAGGGACTGCCATCATCTTGGAATCCAAAATAATTTTGATTACAAGC

GCTTTATTAAGTTTGCCCGTGTCTGTGAAGTAGACAATGAGTTGCGTATTTGT

GCTAGAGATAAGGAAGTTGGAAATCTGTATGACATGTTCCACACTCGCAACT

CTTTACACCGTAGAGCTTATCAACACAAAGTTGGCAACATTATTGATACAATG

ATTACAGATGCTTTCCTCAAAGCAGATGACTACATAGAGATTACAGGTGCTG

GAGGAAAAAAGTATCGCATTTCTACAGCAATTGACGACATGGAAGCCTATAC

TAAGCTGACAGATAACATTTTTCTGGAGATTTTATACTCTACTGATCCCAAAT

TGAAAGACGCACGAGAGATTTTAAAACAAATTGAATACCGTAATCTATTCAA

GTATGTGGGTGAGACGCAGCCAACAGGACAAATAAAGATTAAAAGGGAGGA

CTATGAATCTCTTCCAAAAGAGGTTGCCAGTGCTAAACCCAAAGTATTGCTA

GACGTGAAACTGAAGGCTGAAGATTTTATAGTGGATGTTATCAACATGGATT

ATGGAATGCAAGAAAAGAATCCAATTGATCATGTTAGCTTCTATTGTAAGAC

TGCCCCCAACAGAGCAATCAGGATTACTAAAAACCAGGTTTCACAACTTCTG

CCAGAGAAATTTGCAGAGCAGCTGATTCGAGTATATTGTAAGAAGGTGGACA

GAAAGAGTTTGTATGCCGCAAGACAATATTTTGTTCAGTGGTGTGCAGACAG

AAATTTCACCAAGCCGCAGGATGGCGATGTTATAGCCCCACTCATAACACCT

CAAAAAAAGGAATGGAACGACAGTACTTCAGTCCAAAATCCAACTCGCCTCC

GAGAAGCATCCAAAAGCAGAGTCCAGCTTTTTAAAGATGACCCAATGTGA

Human SAMHD1 Protein Sequence, Variant 1 (SEQ ID NO: 27)

MQRADSEQPSKRPRCDDSPRTPSNTPSAEADWSPGLELHPDYKTWGPEQVCSFL

RRGGFEEPVLLKNIRENEITGALLPCLDESRFENLGVSSLGERKKLLSYIQRLVQIH

VDTMKVINDPIHGHIELHPLLVRIIDTPQFQRLRYIKQLGGGYYVFPGASHNRFEH

SLGVGYLAGCLVHALGEKQPELQISERDVLCVQIAGLCHDLGHGPFSHMFDGRFI

PLARPEVKWTHEQGSVMMFEHLINSNGIKPVMEQYGLIPEEDICFIKEQIVGPLES

PVEDSLWPYI<GRPENI<SFLYEIVSNI<RNGIDVDI<WDYFARD CHHLGIQNNFDYI<

RFIKFARVCEVDNELRICARDKEVGNLYDMFHTRNSLHRRAYQHKVGNIIDTMIT

DAFLKADDYIEITGAGGKKYRISTAIDDMEAYTKLTDNIFLEILYSTDPKLKDARE

ILKQIEYRNLFKYVGETQPTGQIKIKREDYESLPKEVASAKPKVLLDVKLKAEDFI

VDVINMDYGMQEKNPIDHVSFYCKTAPNRAIRITKNQVSQLLPEKFAEQLIRVYC

KKVDRKSLYAARQYFVQWCADRNFTKPQDGDVIAPLITPQKKEWNDSTSVQNP

TRLREASKSRVQLFKDDPM Human SAMHD1 cDNA Sequence, Variant 2 (SEQ ID NO: 28)

ATGCAGCGAGCCGATTCCGAGCAGCCCTCCAAGCGTCCCCGTTGCGATGACA

GCCCGAGAACCCCCTCAAACACCCCTTCCGCAGAGGCAGACTGGTCCCCGGG

CCTGGAACTCCATCCCGACTACAAGACATGGGGTCCGGAGCAGGTGTGCTCC

TTCCTCAGGCGCGGTGGCTTTGAAGAGCCGGTGCTGCTGAAGAACATCCGAG

AAAATGAAATCACAGGCGCATTACTGCCTTGTCTTGATGAGTCTCGTTTTGAA

AATCTTGGAGTAAGTTCCTTGGGGGAGAGGAAGAAGCTGCTTAGTTATATCC

AGCGATTGGTTCAAATCCACGTTGATACAATGAAGGTAATTAATGATCCTATC

CATGGCCACATTGAGCTCCACCCTCTCCTCGTCCGAATCATTGATACACCTCA

ATTTCAACGTCTTCGATACATCAAACAGCTGGGAGGTGGTTACTATGTTTTTC

CAGGAGCTTCACACAATCGATTTGAGCATAGTCTAGGGGTGGGGTATCTAGC

AGGATGTCTAGTTCACGCACTGGGTGAAAAACAACCAGAGCTGCAGATAAGT

GAACGAGATGTTCTCTGTGTTCAGATTGCTGGACTTTGTCATGATCTCGGTCA

TGGGCCATTTTCTCACATGTTTGATGGACGATTTATTCCACTTGCTCGCCCGG

AGGTGAAATGGACGCATGAACAAGGCTCAGTTATGATGTTTGAGCACCTTAT

TAATTCTAATGGAATTAAGCCTGTCATGGAACAATATGGTCTCATCCCTGAAG

AAGATATTTGCTTTATAAAGGAACAAATTGTAGGACCACTTGAATCACCTGTC

GAAGATTCATTGTGGCCATATAAAGGGCGTCCTGAAAACAAAAGCTTCCTTT

ATGAGATAGTATCTAATAAAAGAAATGGCATTGATGTGGACAAATGGGATTA

TTTTGCCAGGGACTGCCATCATCTTGGAATCCAAAATAATTTTGATTACAAGC

GCTTTATTAAGTTTGCCCGTGTCTGTGAAGTAGACAATGAGTTGCGTATTTGT

GCTAGAGATAAGGAAGTTGGAAATCTGTATGACATGTTCCACACTCGCAACT

CTTTACACCGTAGAGCTTATCAACACAAAGTTGGCAACATTATTGATACAATG

ATTACAGATGCTTTCCTCAAAGCAGATGACTACATAGAGATTACAGGTGCTG

GAGGAAAAAAGTATCGCATTTCTACAGCAATTGACGACATGGAAGCCTATAC

TAAGCTGACAGATAACATTTTTCTGGAGATTTTATACTCTACTGATCCCAAAT

TGAAAGACGCACGAGAGATTTTAAAACAAATTGAATACCGTAATCTATTCAA

GTATGTGGGTGAGACGCAGCCAACAGGACAAATAAAGATTAAAAGGGAGGA

CTATGAATCTCTTCCAAAAGAGGTTGCCAGTGCTAAACCCAAAGTATTGCTA

GACGTGAAACTGAAGGCTGAAGATTTTATAGTGGATGTTTCACAACTTCTGCC

AGAGAAATTTGCAGAGCAGCTGATTCGAGTATATTGTAAGAAGGTGGACAGA

AAGAGTTTGTATGCCGCAAGACAATATTTTGTTCAGTGGTGTGCAGACAGAA

ATTTCACCAAGCCGCAGGATGGCGATGTTATAGCCCCACTCATAACACCTCA

AAAAAAGGAATGGAACGACAGTACTTCAGTCCAAAATCCAACTCGCCTCCGA

GAAGCATCCAAAAGCAGAGTCCAGCTTTTTAAAGATGACCCAATGTGA

Human SAMHD1 Protein Sequence, Variant 2 (SEQ ID NO: 29)

MQRADSEQPSKRPRCDDSPRTPSNTPSAEADWSPGLELHPDYKTWGPEQVCSFL

RRGGFEEPVLLKNIRENEITGALLPCLDESRFENLGVSSLGERKKLLSYIQRLVQIH

VDTMKVINDPIHGHIELHPLLVRIIDTPQFQRLRYIKQLGGGYYVFPGASHNRFEH

SLGVGYLAGCLVHALGEKQPELQISERDVLCVQIAGLCHDLGHGPFSHMFDGRFI

PLARPEVKWTHEQGSVMMFEHLINSNGIKPVMEQYGLIPEEDICFIKEQIVGPLES

PVEDSLWPYKGRPENKSFLYEIVSNKRNGIDVDKWDYFARDCHHLGIQNNFDYK RFIKFARVCEVDNELRICARDKEVGNLYDMFHTRNSLHRRAYQHKVGNIIDTMIT

DAFLKADDYIEITGAGGKKYRISTAIDDMEAYTKLTDNIFLEILYSTDPKLKDARE

ILKQIEYRNLFKYVGETQPTGQIKIKREDYESLPKEVASAKPKVLLDVKLKAEDFI

VDVSQLLPEKFAEQLIRVYCKKVDRKSLYAARQYFVQWCADRNFTKPQDGDVI

APLITPQKKEWNDSTSVQNPTRLREASKSRVQLFKDDPM

Human SAMHD1 cDNA Sequence, Variant 3 (SEQ ID NO: 30)

ATGCAGCGAGCCGATTCCGAGCAGCCCTCCAAGCGTCCCCGTTGCGATGACA

GCCCGAGAACCCCCTCAAACACCCCTTCCGCAGAGGCAGACTGGTCCCCGGG

CCTGGAACTCCATCCCGACTACAAGACATGGGGTCCGGAGCAGGTGTGCTCC

TTCCTCAGGCGCGGTGGCTTTGAAGAGCCGGTGCTGCTGAAGAACATCCGAG

AAAATGAAATCACAGGCGCATTACTGCCTTGTCTTGATGAGTCTCGTTTTGAA

AATCTTGGAGTAAGTTCCTTGGGGGAGAGGAAGAAGCTGCTTAGTTATATCC

AGCGATTGGTTCAAATCCACGTTGATACAATGAAGGTAATTAATGATCCTATC

CATGGCCACATTGAGCTCCACCCTCTCCTCGTCCGAATCATTGATACACCTCA

ATTTCAACGTCTTCGATACATCAAACAGCTGGGAGGTGGTTACTATGTTTTTC

CAGGAGCTTCACACAATCGATTTGAGCATAGTCTAGGGGTGGGGTATCTAGC

AGGATGTCTAGTTCACGCACTGGGTGAAAAACAACCAGAGCTGCAGATAAGT

GAACGAGATGTTCTCTGTGTTCAGATTGCTGGACTTTGTCATGATCTCGGTCA

TGGGCCATTTTCTCACATGTTTGATGGACGATTTATTCCACTTGCTCGCCCGG

AGGTGAAATGGACGCATGAACAAGGCTCAGTTATGATGTTTGAGCACCTTAT

TAATTCTAATGGAATTAAGCCTGTCATGGAACAATATGGTCTCATCCCTGAAG

AAGATATTTGCTTTATAAAGGAACAAATTGTAGGACCACTTGAATCACCTGTC

GAAGATTCATTGTGGCCATATAAAGGGCGTCCTGAAAACAAAAGCTTCCTTT

ATGAGATAGTATCTAATAAAAGAAATGGCATTGATGTGGACAAATGGGATTA

TTTTGCCAGGGACTGCCATCATCTTGGAATCCAAAATAATTTTGATTACAAGC

GCTTTATTAAGTTTGCCCGTGTCTGTGAAGTAGACAATGAGTTGCGTATTTGT

GCTAGAGATAAGGAAGTTGGAAATCTGTATGACATGTTCCACACTCGCAACT

CTTTACACCGTAGAGCTTATCAACACAAAGTTGGCAACATTATTGATACAATG

ATTACAGATGCTTTCCTCAAAGCAGATGACTACATAGAGATTACAGGTGCTG

GAGGAAAAAAGTATCGCATTTCTACAGCAATTGACGACATGGAAGCCTATAC

TAAGCTGACAGATAACATTTTTCTGGAGATTTTATACTCTACTGATCCCAAAT

TGAAAGACGCACGAGAGATTTTAAAACAAATTGAATACCGTAATCTATTCAA

GTATGTGGGTGAGACGCAGCCAACAGGACAAATAAAGATTAAAAGGGAGGA

CTATGAATCTCTTCCAAAAGAGGTTGCCAGTGCTAAACCCAAAGTATTGCTA

GACGTGAAACTGAAGGCTGAAGATTTTATAGTGGATGTTATCAACATGGATT

ATGGAATGCAAGAAAAGAATCCAATTGATCATGTTAGCTTCTATTGTAAGAC

TGCCCCCAACAGAGCAATCAGGATTACTAAAAACCAGGTTTCACAACTTCTG

CCAGAGAAATTTGCAGAGCAGCTGATTCGAGTATATTGTAAGAAGGTGGACA

GAAAGAGTTTGTATGCCGCAAGACAATATTTTGTTCAGTGGTGTGCAGACAG

AAATTTCACCAAGCCGCAGTCTCCCACCAGAGCCTCCCACTGA Human SAMHD1 Protein Sequence, Variant 3 (SEQ ID NO: 31)

MQRADSEQPSKRPRCDDSPRTPSNTPSAEADWSPGLELHPDYKTWGPEQVCSFL RRGGFEEPVLLKNIRENEITGALLPCLDESRFENLGVSSLGERKKLLSYIQRLVQIH VDTMKVINDPIHGHIELHPLLVRIIDTPQFQRLRYIKQLGGGYYVFPGASHNRFEH SLGVGYLAGCLVHALGEKQPELQISERDVLCVQIAGLCHDLGHGPFSHMFDGRFI PLARPEVKWTHEQGSVMMFEHLINSNGIKPVMEQYGLIPEEDICFIKEQIVGPLES PVEDSLWPYI<GRPENI<SFLYEIVSNI<RNGIDVDI<WDYFARDCHH LGIQNNFDYI< RFIKFARVCEVDNELRICARDKEVGNLYDMFHTRNSLHRRAYQHKVGNIIDTMIT DAFLKADDYIEITGAGGKKYRISTAIDDMEAYTKLTDNIFLEILYSTDPKLKDARE

ILKQIEYRNLFKYVGETQPTGQIKIKREDYESLPKEVASAKPKVLLDVKLKAEDFI VDVINMDYGMQEKNPIDHVSFYCKTAPNRAIRITKNQVSQLLPEKFAEQLIRVYC KKVDRKSLYAARQYFVQWCADRNFTKPQSPTRASH

Human DNASE2 Precursor cDNA Sequence (SEQ ID NO: 32)

ATGATCCCGCTGCTGCTGGCAGCGCTGCTGTGCGTCCCCGCCGGGGCCCTGA CCTGCTACGGGGACTCCGGGCAGCCTGTAGACTGGTTCGTGGTCTACAAGCT GCCAGCTCTTAGAGGGTCCGGGGAGGCGGCGCAGAGAGGGCTGCAGTACAA GTATCTGGACGAGAGCTCCGGAGGCTGGCGGGACGGCAGGGCACTCATCAA CAGCCCGGAGGGGGCCGTGGGCCGAAGCCTGCAGCCGCTGTACCGGAGCAA CACCAGCCAGCTCGCCTTCCTGCTCTACAATGACCAACCGCCTCAACCCAGC AAGGCTCAGGACTCTTCCATGCGTGGGCACACGAAGGGTGTCCTGCTCCTTG ACCACGATGGGGGCTTCTGGCTGGTCCACAGTGTACCTAACTTCCCTCCACCG

GCCTCCTCTGCTGCATACAGCTGGCCTCATAGCGCCTGTACCTACGGGCAGAC CCTGCTCTGTGTGTCTTTTCCCTTCGCTCAGTTCTCGAAGATGGGCAAGCAGC TGACCTACACCTACCCCTGGGTCTATAACTACCAGCTGGAAGGGATCTTTGCC CAGGAATTCCCCGACTTGGAGAATGTGGTCAAGGGCCACCACGTTAGCCAAG AACCCTGGAACAGCAGCATCACACTCACATCCCAGGCCGGGGCTGTTTTCCA GAGCTTTGCCAAGTTCAGCAAATTTGGAGATGACCTGTACTCCGGCTGGTTGG CAGCAGCCCTTGGTACCAACCTGCAGGTCCAGTTCTGGCACAAAACTGTAGG CATCCTGCCCTCTAACTGCTCGGATATCTGGCAGGTTCTGAATGTGAACCAGA

TAGCTTTCCCTGGACCAGCCGGCCCAAGCTTCAACAGCACAGAGGACCACTC CAAATGGTGCGTGTCCCCAAAAGGGCCCTGGACCTGCGTGGGTGACATGAAT CGGAACCAGGGAGAGGAGCAACGGGGTGGGGGCACACTGTGTGCCCAGCTG CCAGCCCTCTGGAAAGCCTTCCAGCCGCTGGTGAAGAACTACCAGCCCTGTA ATGGCATGGCCAGGAAGCCCAGCAGAGCTTATAAGATCTAA

Human DNASE2 Precursor Protein Sequence (SEQ ID NO: 33)

MIPLLLAALLCVPAGALTCYGDSGQPVDWFVVYKLPALRGSGEAAQRGLQYKY LDESSGGWRDGRALINSPEGAVGRSLQPLYRSNTSQLAFLLYNDQPPQPSKAQDS SMRGHTKGVLLLDHDGGFWLVHSVPNFPPPASSAAYSWPHSACTYGQTLLCVSF PF AQF SKMGKQLTYTYPWVYNYQLEGIF AQEFPDLENVVKGHHVSQEPWNS SIT LTSQAGAVFQSFAKFSKFGDDLYSGWLAAALGTNLQVQFWHKTVGILPSNCSDI WQVLNVNQIAFPGPAGPSFNSTEDHSKWCVSPKGPWTCVGDMNRNQGEEQRG

GGTLCAQLPALWKAFQPLVKNYQPCNGMARKPSRAYKI

Human DNASE2 Mature cDNA Sequence (SEQ ID NO: 34)

TGCTACGGGGACTCCGGGCAGCCTGTAGACTGGTTCGTGGTCTACAAGCTGC

CAGCTCTTAGAGGGTCCGGGGAGGCGGCGCAGAGAGGGCTGCAGTACAAGT

ATCTGGACGAGAGCTCCGGAGGCTGGCGGGACGGCAGGGCACTCATCAACA

GCCCGGAGGGGGCCGTGGGCCGAAGCCTGCAGCCGCTGTACCGGAGCAACA

CCAGCCAGCTCGCCTTCCTGCTCTACAATGACCAACCGCCTCAACCCAGCAA

GGCTCAGGACTCTTCCATGCGTGGGCACACGAAGGGTGTCCTGCTCCTTGAC

CACGATGGGGGCTTCTGGCTGGTCCACAGTGTACCTAACTTCCCTCCACCGGC

CTCCTCTGCTGCATACAGCTGGCCTCATAGCGCCTGTACCTACGGGCAGACCC

TGCTCTGTGTGTCTTTTCCCTTCGCTCAGTTCTCGAAGATGGGCAAGCAGCTG

ACCTACACCTACCCCTGGGTCTATAACTACCAGCTGGAAGGGATCTTTGCCCA

GGAATTCCCCGACTTGGAGAATGTGGTCAAGGGCCACCACGTTAGCCAAGAA

CCCTGGAACAGCAGCATCACACTCACATCCCAGGCCGGGGCTGTTTTCCAGA

GCTTTGCCAAGTTCAGCAAATTTGGAGATGACCTGTACTCCGGCTGGTTGGCA

GCAGCCCTTGGTACCAACCTGCAGGTCCAGTTCTGGCACAAAACTGTAGGCA

TCCTGCCCTCTAACTGCTCGGATATCTGGCAGGTTCTGAATGTGAACCAGATA

GCTTTCCCTGGACCAGCCGGCCCAAGCTTCAACAGCACAGAGGACCACTCCA

AATGGTGCGTGTCCCCAAAAGGGCCCTGGACCTGCGTGGGTGACATGAATCG

GAACCAGGGAGAGGAGCAACGGGGTGGGGGCACACTGTGTGCCCAGCTGCC

AGCCCTCTGGAAAGCCTTCCAGCCGCTGGTGAAGAACTACCAGCCCTGTAAT

GGCATGGCCAGGAAGCCCAGCAGAGCTTATAAGATCTAA

Human DNASE2 Mature Protein Sequence (SEQ ID NO: 35)

CYGDSGQPVDWFVVYKLPALRGSGEAAQRGLQYKYLDESSGGWRDGRALINSP

EGAVGRSLQPLYRSNTSQLAFLLYNDQPPQPSKAQDSSMRGHTKGVLLLDHDGG

FWLVHSVPNFPPPASSAAYSWPHSACTYGQTLLCVSFPFAQFSKMGKQLTYTYP

WVYNYQLEGIFAQEFPDLENVVKGHHVSQEPWNSSITLTSQAGAVFQSFAKFSK

FGDDLYSGWLAAALGTNLQVQFWHKTVGILPSNCSDIWQVLNVNQIAFPGPAGP

SFNSTEDHSKWCVSPKGPWTCVGDMNRNQGEEQRGGGTLCAQLPALWKAFQP

LVKNYQPCNGMARKPSRAYKI

Human BLM cDNA Sequence, Variant 1 (SEQ ID NO: 36)

ATGGCTGCTGTTCCTCAAAATAATCTACAGGAGCAACTAGAACGTCACTCAG

CCAGAACACTTAATAATAAATTAAGTCTTTCAAAACCAAAATTTTCAGGTTTC

ACTTTTAAAAAGAAAACATCTTCAGATAACAATGTATCTGTAACTAATGTGTC

AGTAGCAAAAACACCTGTATTAAGAAATAAAGATGTTAATGTTACCGAAGAC

TTTTCCTTCAGTGAACCTCTACCCAACACCACAAATCAGCAAAGGGTCAAGG

ACTTCTTTAAAAATGCTCCAGCAGGACAGGAAACACAGAGAGGTGGATCAAA

ATCATTATTGCCAGATTTCTTGCAGACTCCGAAGGAAGTTGTATGCACTACCC AAAACACACCAACTGTAAAGAAATCCCGGGATACTGCTCTCAAGAAATTAGA

ATTTAGTTCTTCACCAGATTCTTTAAGTACCATCAATGATTGGGATGATATGG

ATGACTTTGATACTTCTGAGACTTCAAAATCATTTGTTACACCACCCCAAAGT

CACTTTGTAAGAGTAAGCACTGCTCAGAAATCAAAAAAGGGTAAGAGAAACT

TTTTTAAAGCACAGCTTTATACAACAAACACAGTAAAGACTGATTTGCCTCCA

CCCTCCTCTGAAAGCGAGCAAATAGATTTGACTGAGGAACAGAAGGATGACT

CAGAATGGTTAAGCAGCGATGTGATTTGCATCGATGATGGCCCCATTGCTGA

AGTGCATATAAATGAAGATGCTCAGGAAAGTGACTCTCTGAAAACTCATTTG

GAAGATGAAAGAGATAATAGCGAAAAGAAGAAGAATTTGGAAGAAGCTGAA

TTACATTCAACTGAGAAAGTTCCATGTATTGAATTTGATGATGATGATTATGA

TACGGATTTTGTTCCACCTTCTCCAGAAGAAATTATTTCTGCTTCTTCTTCCTC

TTCAAAATGCCTTAGTACGTTAAAGGACCTTGACACCTCTGACAGAAAAGAG

GATGTTCTTAGCACATCAAAAGATCTTTTGTCAAAACCTGAGAAAATGAGTA

TGCAGGAGCTGAATCCAGAAACCAGCACAGACTGTGACGCTAGACAGATAA

GTTTACAGCAGCAGCTTATTCATGTGATGGAGCACATCTGTAAATTAATTGAT

ACTATTCCTGATGATAAACTGAAACTTTTGGATTGTGGGAACGAACTGCTTCA

GCAGCGGAACATAAGAAGGAAACTTCTAACGGAAGTAGATTTTAATAAAAGT

GATGCCAGTCTTCTTGGCTCATTGTGGAGATACAGGCCTGATTCACTTGATGG

CCCTATGGAGGGTGATTCCTGCCCTACAGGGAATTCTATGAAGGAGTTAAAT

TTTTCACACCTTCCCTCAAATTCTGTTTCTCCTGGGGACTGTTTACTGACTACC

ACCCTAGGAAAGACAGGATTCTCTGCCACCAGGAAGAATCTTTTTGAAAGGC

CTTTATTCAATACCCATTTACAGAAGTCCTTTGTAAGTAGCAACTGGGCTGAA

ACACCAAGACTAGGAAAAAAAAATGAAAGCTCTTATTTCCCAGGAAATGTTC

TCACAAGCACTGCTGTGAAAGATCAGAATAAACATACTGCTTCAATAAATGA

CTTAGAAAGAGAAACCCAACCTTCCTATGATATTGATAATTTTGACATAGATG

ACTTTGATGATGATGATGACTGGGAAGACATAATGCATAATTTAGCAGCCAG

CAAATCTTCCACAGCTGCCTATCAACCCATCAAGGAAGGTCGGCCAATTAAA

TCAGTATCAGAAAGACTTTCCTCAGCCAAGACAGACTGTCTTCCAGTGTCATC

TACTGCTCAAAATATAAACTTCTCAGAGTCAATTCAGAATTATACTGACAAGT

CAGCACAAAATTTAGCATCCAGAAATCTGAAACATGAGCGTTTCCAAAGTCT

TAGTTTTCCTCATACAAAGGAAATGATGAAGATTTTTCATAAAAAATTTGGCC

TGCATAATTTTAGAACTAATCAGCTAGAGGCGATCAATGCTGCACTGCTTGGT

GAAGACTGTTTTATCCTGATGCCGACTGGAGGTGGTAAGAGTTTGTGTTACCA

GCTCCCTGCCTGTGTTTCTCCTGGGGTCACTGTTGTCATTTCTCCCTTGAGATC

ACTTATCGTAGATCAAGTCCAAAAGCTGACTTCCTTGGATATTCCAGCTACAT

ATCTGACAGGTGATAAGACTGACTCAGAAGCTACAAATATTTACCTCCAGTT

ATCAAAAAAAGACCCAATCATAAAACTTCTATATGTCACTCCAGAAAAGATC

TGTGCAAGTAACAGACTCATTTCTACTCTGGAGAATCTCTATGAGAGGAAGC

TCTTGGCACGTTTTGTTATTGATGAAGCACATTGTGTCAGTCAGTGGGGACAT

GATTTTCGTCAAGATTACAAAAGAATGAATATGCTTCGCCAGAAGTTTCCTTC

TGTTCCGGTGATGGCTCTTACGGCCACAGCTAATCCCAGGGTACAGAAGGAC

ATCCTGACTCAGCTGAAGATTCTCAGACCTCAGGTGTTTAGCATGAGCTTTAA

CAGACATAATCTGAAATACTATGTATTACCGAAAAAGCCTAAAAAGGTGGCA

TTTGATTGCCTAGAATGGATCAGAAAGCACCACCCATATGATTCAGGGATAA

TTTACTGCCTCTCCAGGCGAGAATGTGACACCATGGCTGACACGTTACAGAG AGATGGGCTCGCTGCTCTTGCTTACCATGCTGGCCTCAGTGATTCTGCCAGAG

ATGAAGTGCAGCAGAAGTGGATTAATCAGGATGGCTGTCAGGTTATCTGTGC

TACAATTGCATTTGGAATGGGGATTGACAAACCGGACGTGCGATTTGTGATT

CATGCATCTCTCCCTAAATCTGTGGAGGGTTACTACCAAGAATCTGGCAGAG

CTGGAAGAGATGGGGAAATATCTCACTGCCTGCTTTTCTATACCTATCATGAT

GTGACCAGACTGAAAAGACTTATAATGATGGAAAAAGATGGAAACCATCAT

ACAAGAGAAACTCACTTCAATAATTTGTATAGCATGGTACATTACTGTGAAA

ATATAACGGAATGCAGGAGAATACAGCTTTTGGCCTACTTTGGTGAAAATGG

ATTTAATCCTGATTTTTGTAAGAAACACCCAGATGTTTCTTGTGATAATTGCT

GTAAAACAAAGGATTATAAAACAAGAGATGTGACTGACGATGTGAAAAGTA

TTGTAAGATTTGTTCAAGAACATAGTTCATCACAAGGAATGAGAAATATAAA

ACATGTAGGTCCTTCTGGAAGATTTACTATGAATATGCTGGTCGACATTTTCT

TGGGGAGTAAGAGTGCAAAAATCCAGTCAGGTATATTTGGAAAAGGATCTGC

TTATTCACGACACAATGCCGAAAGACTTTTTAAAAAGCTGATACTTGACAAG

ATTTTGGATGAAGACTTATATATCAATGCCAATGACCAGGCGATCGCTTATGT

GATGCTCGGAAATAAAGCCCAAACTGTACTAAATGGCAATTTAAAGGTAGAC

TTTATGGAAACAGAAAATTCCAGCAGTGTGAAAAAACAAAAAGCGTTAGTAG

CAAAAGTGTCTCAGAGGGAAGAGATGGTTAAAAAATGTCTTGGAGAACTTAC

AGAAGTCTGCAAATCTCTGGGGAAAGTTTTTGGTGTCCATTACTTCAATATTT

TTAATACCGTCACTCTCAAGAAGCTTGCAGAATCTTTATCTTCTGATCCTGAG

GTTTTGCTTCAAATTGATGGTGTTACTGAAGACAAACTGGAAAAATATGGTG

CGGAAGTGATTTCAGTATTACAGAAATACTCTGAATGGACATCGCCAGCTGA

AGACAGTTCCCCAGGGATAAGCCTGTCCAGCAGCAGAGGCCCCGGAAGAAG

TGCCGCTGAGGAGCTCGACGAGGAAATACCCGTATCTTCCCACTACTTTGCA

AGTAAAACCAGAAATGAAAGGAAGAGGAAAAAGATGCCAGCCTCCCAAAGG

TCTAAGAGGAGAAAAACTGCTTCCAGTGGTTCCAAGGCAAAGGGGGGGTCTG

CCACATGTAGAAAGATATCTTCCAAAACGAAATCCTCCAGCATCATTGGATC

CAGTTCAGCCTCACATACTTCTCAAGCGACATCAGGAGCCAATAGCAAATTG

GGGATTATGGCTCCACCGAAGCCTATAAATAGACCGTTTCTTAAGCCTTCATA

TGCATTCTCATAA

Human BLM Protein Sequence, Variant 1 (SEQ ID NO: 37)

MAAVPQNNLQEQLERHSARTLNNKLSLSKPKFSGFTFKKKTSSDNNVSVTNVSV

AKTPVLRNKDVNVTEDF SF SEPLPNTTNQQRVKDFFKNAP AGQETQRGGSKSLL

PDFLQTPKEVVCTTQNTPTVKKSRDTALKKLEFSSSPDSLSTINDWDDMDDFDTS

ETSKSFVTPPQSHFVRVSTAQKSKKGKRNFFKAQLYTTNTVKTDLPPPSSESEQID

LTEEQKDDSEWLSSDVICIDDGPIAEVHINEDAQESDSLKTHLEDERDNSEKKKN

LEEAELHSTEKVPCIEFDDDDYDTDF VPPSPEEIIS AS S S SSKCLSTLKDLDTSDRK

EDVLSTSKDLLSKPEKMSMQELNPETSTDCDARQISLQQQLIHVMEHICKLIDTIP

DDKLKLLDCGNELLQQRNIRRKLLTEVDFNKSDASLLGSLWRYRPDSLDGPMEG

DSCPTGNSMKELNFSHLPSNSVSPGDCLLTTTLGKTGFSATRKNLFERPLFNTHL

QKSFVSSNWAETPRLGKKNESSYFPGNVLTSTAVKDQNKHTASINDLERETQPSY

DIDNFDIDDFDDDDDWEDIMHNLAASKSSTAAYQPIKEGRPIKSVSERLSSAKTD

CLPVSSTAQNINFSESIQNYTDKSAQNLASRNLKHERFQSLSFPHTKEMMKIFHK KFGLHNFRTNQLEAINAALLGEDCFILMPTGGGKSLCYQLPACVSPGVTVVISPL RSLIVDQVQKLTSLDIPATYLTGDKTDSEATNIYLQLSKKDPIIKLLYVTPEKICAS NRLISTLENLYERKLLARFVIDEAHCVSQWGHDFRQDYKRMNMLRQKFPSVPV MALTATANPRVQKDILTQLKILRPQVFSMSFNRHNLKYYVLPKKPKKVAFDCLE WIRKHHPYDSGIIYCLSRRECDTMADTLQRDGLAALAYHAGLSDSARDEVQQK WINQDGCQVICATIAFGMGIDKPDVRFVIHASLPKSVEGYYQESGRAGRDGEISH CLLFYTYHDVTRLKRLIMMEKDGNHHTRETHFNNLYSMVHYCENITECRRIQLL AYFGENGFNPDFCKKHPDVSCDNCCKTKDYKTRDVTDDVKSIVRFVQEHSSSQG MRNIKHVGPSGRFTMNMLVDIFLGSKSAKIQSGIFGKGSAYSRHNAERLFKKLIL DKILDEDL YINANDQ AIA YVMLGNK AQT VLNGNLKVDFMETENS S S VKKQKAL VAKVSQREEMVKKCLGELTEVCKSLGKVFGVHYFNIFNTVTLKKLAESLSSDPE VLLQIDGVTEDKLEKYGAEVISVLQKYSEWTSPAEDSSPGISLSSSRGPGRSAAEE LDEEIPVSSHYFASKTRNERKRKKMPASQRSKRRKTASSGSKAKGGSATCRKISS KTKS S SIIGS S S ASHTSQ AT SGANSKLGIMAPPKPINRPFLKP S YAF S

Human BLM cDNA Sequence, Variant 2 (SEQ ID NO: 38)

ATGGCTGCTGTTCCTCAAAATAATCTACAGGAGCAACTAGAACGTCACTCAG CCAGAACACTTAATAATAAATTAAGTCTTTCAAAACCAAAATTTTCAGGTTTC ACTTTTAAAAAGAAAACATCTTCAGATAACAATGTATCTGTAACTAATGTGTC AGTAGCAAAAACACCTGTATTAAGAAATAAAGATGTTAATGTTACCGAAGAC TTTTCCTTCAGTGAACCTCTACCCAACACCACAAATCAGCAAAGGGTCAAGG ACTTCTTTAAAAATGCTCCAGCAGGACAGGAAACACAGAGAGGTGGATCAAA ATCATTATTGCCAGATTTCTTGCAGACTCCGAAGGAAGTTGTATGCACTACCC AAAACACACCAACTGTAAAGAAATCCCGGGATACTGCTCTCAAGAAATTAGA ATTTAGTTCTTCACCAGATTCTTTAAGTACCATCAATGATTGGGATGATATGG ATGACTTTGATACTTCTGAGACTTCAAAATCATTTGTTACACCACCCCAAAGT CACTTTGTAAGAGTAAGCACTGCTCAGAAATCAAAAAAGGGTAAGAGAAACT TTTTTAAAGCACAGCTTTATACAACAAACACAGTAAAGACTGATTTGCCTCCA CCCTCCTCTGAAAGCGAGCAAATAGATTTGACTGAGGAACAGAAGGATGACT CAGAATGGTTAAGCAGCGATGTGATTTGCATCGATGATGGCCCCATTGCTGA AGTGCATATAAATGAAGATGCTCAGGAAAGTGACTCTCTGAAAACTCATTTG GAAGATGAAAGAGATAATAGCGAAAAGAAGAAGAATTTGGAAGAAGCTGAA TTACATTCAACTGAGAAAGTTCCATGTATTGAATTTGATGATGATGATTATGA TACGGATTTTGTTCCACCTTCTCCAGAAGAAATTATTTCTGCTTCTTCTTCCTC

TTCAAAATGCCTTAGTACGTTAAAGGACCTTGACACCTCTGACAGAAAAGAG GATGTTCTTAGCACATCAAAAGATCTTTTGTCAAAACCTGAGAAAATGAGTA TGCAGGAGCTGAATCCAGAAACCAGCACAGACTGTGACGCTAGACAGATAA GTTTACAGCAGCAGCTTATTCATGTGATGGAGCACATCTGTAAATTAATTGAT ACTATTCCTGATGATAAACTGAAACTTTTGGATTGTGGGAACGAACTGCTTCA GCAGCGGAACATAAGAAGGAAACTTCTAACGGAAGTAGATTTTAATAAAAGT GATGCCAGTCTTCTTGGCTCATTGTGGAGATACAGGCCTGATTCACTTGATGG CCCTATGGAGGGTGATTCCTGCCCTACAGGGAATTCTATGAAGGAGTTAAAT TTTTCACACCTTCCCTCAAATTCTGTTTCTCCTGGGGACTGTTTACTGACTACC ACCCTAGGAAAGACAGGATTCTCTGCCACCAGGAAGAATCTTTTTGAAAGGC CTTTATTCAATACCCATTTACAGAAGTCCTTTGTAAGTAGCAACTGGGCTGAA

ACACCAAGACTAGGAAAAAAAAATGAAAGCTCTTATTTCCCAGGAAATGTTC

TCACAAGCACTGCTGTGAAAGATCAGAATAAACATACTGCTTCAATAAATGA

CTTAGAAAGAGAAACCCAACCTTCCTATGATATTGATAATTTTGACATAGATG

ACTTTGATGATGATGATGACTGGGAAGACATAATGCATAATTTAGCAGCCAG

CAAATCTTCCACAGCTGCCTATCAACCCATCAAGGAAGGTCGGCCAATTAAA

TCAGTATCAGAAAGACTTTCCTCAGCCAAGACAGACTGTCTTCCAGTGTCATC

TACTGCTCAAAATATAAACTTCTCAGAGTCAATTCAGAATTATACTGACAAGT

CAGCACAAAATTTAGCATCCAGAAATCTGAAACATGAGCGTTTCCAAAGTCT

TAGTTTTCCTCATACAAAGGAAATGATGAAGATTTTTCATAAAAAATTTGGCC

TGCATAATTTTAGAACTAATCAGCTAGAGGCGATCAATGCTGCACTGCTTGGT

GAAGACTGTTTTATCCTGATGCCGACTGGAGGTGGTAAGAGTTTGTGTTACCA

GCTCCCTGCCTGTGTTTCTCCTGGGGTCACTGTTGTCATTTCTCCCTTGAGATC

ACTTATCGTAGATCAAGTCCAAAAGCTGACTTCCTTGGATATTCCAGCTACAT

ATCTGACAGGTGATAAGACTGACTCAGAAGCTACAAATATTTACCTCCAGTT

ATCAAAAAAAGACCCAATCATAAAACTTCTATATGTCACTCCAGAAAAGATC

TGTGCAAGTAACAGACTCATTTCTACTCTGGAGAATCTCTATGAGAGGAAGC

TCTTGGCACGTTTTGTTATTGATGAAGCACATTGTGTCAGTCAGTGGGGACAT

GATTTTCGTCAAGATTACAAAAGAATGAATATGCTTCGCCAGAAGTTTCCTTC

TGTTCCGGTGATGGCTCTTACGGCCACAGCTAATCCCAGGGTACAGAAGGAC

ATCCTGACTCAGCTGAAGATTCTCAGACCTCAGGTGTTTAGCATGAGCTTTAA

CAGACATAATCTGAAATACTATGTATTACCGAAAAAGCCTAAAAAGGTGGCA

TTTGATTGCCTAGAATGGATCAGAAAGCACCACCCATATGATTCAGGGATAA

TTTACTGCCTCTCCAGGCGAGAATGTGACACCATGGCTGACACGTTACAGAG

AGATGGGCTCGCTGCTCTTGCTTACCATGCTGGCCTCAGTGATTCTGCCAGAG

ATGAAGTGCAGCAGAAGTGGATTAATCAGGATGGCTGTCAGGTTATCTGTGC

TACAATTGCATTTGGAATGGGGATTGACAAACCGGACGTGCGATTTGTGATT

CATGCATCTCTCCCTAAATCTGTGGAGGGTTACTACCAAGAATCTGGCAGAG

CTGGAAGAGATGGGGAAATATCTCACTGCCTGCTTTTCTATACCTATCATGAT

GTGACCAGACTGAAAAGACTTATAATGATGGAAAAAGATGGAAACCATCAT

ACAAGAGAAACTCACTTCAATAATTTGTATAGCATGGTACATTACTGTGAAA

ATATAACGGAATGCAGGAGAATACAGCTTTTGGCCTACTTTGGTGAAAATGG

ATTTAATCCTGATTTTTGTAAGAAACACCCAGATGTTTCTTGTGATAATTGCT

GTAAAACAAAGGATTATAAAACAAGAGATGTGACTGACGATGTGAAAAGTA

TTGTAAGATTTGTTCAAGAACATAGTTCATCACAAGGAATGAGAAATATAAA

ACATGTAGGTCCTTCTGGAAGATTTACTATGAATATGCTGGTCGACATTTTCT

TGGAATCTTTATCTTCTGATCCTGAGGTTTTGCTTCAAATTGATGGTGTTACTG

AAGACAAACTGGAAAAATATGGTGCGGAAGTGATTTCAGTATTACAGAAATA

CTCTGAATGGACATCGCCAGCTGAAGACAGTTCCCCAGGGATAAGCCTGTCC

AGCAGCAGAGGCCCCGGAAGAAGTGCCGCTGAGGAGCTCGACGAGGAAATA

CCCGTATCTTCCCACTACTTTGCAAGTAAAACCAGAAATGAAAGGAAGAGGA

AAAAGATGCCAGCCTCCCAAAGGTCTAAGAGGAGAAAAACTGCTTCCAGTGG

TTCCAAGGCAAAGGGGGGGTCTGCCACATGTAGAAAGATATCTTCCAAAACG

AAATCCTCCAGCATCATTGGATCCAGTTCAGCCTCACATACTTCTCAAGCGAC ATCAGGAGCCAATAGCAAATTGGGGATTATGGCTCCACCGAAGCCTATAAAT

AGACCGTTTCTTAAGCCTTCATATGCATTCTCATAA

Human BLM Protein Sequence, Variant 2 (SEQ ID NO: 39)

MAAVPQNNLQEQLERHSARTLNNKLSLSKPKFSGFTFKKKTSSDNNVSVTNVSV AKTPVLRNKDVNVTEDF SF SEPLPNTTNQQRVKDFFKNAP AGQETQRGGSKSLL PDFLQTPKEVVCTTQNTPTVKKSRDTALKKLEFSSSPDSLSTINDWDDMDDFDTS ETSKSFVTPPQSHFVRVSTAQKSKKGKRNFFKAQLYTTNTVKTDLPPPSSESEQID LTEEQKDDSEWLSSDVICIDDGPIAEVHINEDAQESDSLKTHLEDERDNSEKKKN LEEAELHSTEKVPCIEFDDDDYDTDFVPPSPEEIISASSSSSKCLSTLKDLDTSDRK EDVLSTSKDLLSKPEKMSMQELNPETSTDCDARQISLQQQLIHVMEHICKLIDTIP

DDKLKLLDCGNELLQQRNIRRKLLTEVDFNKSDASLLGSLWRYRPDSLDGPMEG DSCPTGNSMKELNFSHLPSNSVSPGDCLLTTTLGKTGFSATRKNLFERPLFNTHL

QKSFVSSNWAETPRLGKKNESSYFPGNVLTSTAVKDQNKHTASINDLERETQPSY DIDNFDIDDFDDDDDWEDIMHNLAASKSSTAAYQPIKEGRPIKSVSERLSSAKTD

CLPVSSTAQNINFSESIQNYTDKSAQNLASRNLKHERFQSLSFPHTKEMMKIFHK KFGLHNFRTNQLEAINAALLGEDCFILMPTGGGKSLCYQLPACVSPGVTVVISPL

RSLIVDQVQKLTSLDIPATYLTGDKTDSEATNIYLQLSKKDPIIKLLYVTPEKICAS NRLISTLENLYERKLLARFVIDEAHCVSQWGHDFRQDYKRMNMLRQKFPSVPV MALTATANPRVQKDILTQLKILRPQVFSMSFNRHNLKYYVLPKKPKKVAFDCLE WIRKHHPYDSGIIYCLSRRECDTMADTLQRDGLAALAYHAGLSDSARDEVQQK WINQDGCQVICATIAFGMGIDKPDVRFVIHASLPKSVEGYYQESGRAGRDGEISH CLLFYTYHDVTRLKRLIMMEKDGNHHTRETHFNNLYSMVHYCENITECRRIQLL

AYFGENGFNPDFCKKHPDVSCDNCCKTKDYKTRDVTDDVKSIVRFVQEHSSSQG MRNIKHVGPSGRFTMNMLVDIFLESLSSDPEVLLQIDGVTEDKLEKYGAEVISVL QKYSEWTSPAEDSSPGISLSSSRGPGRSAAEELDEEIPVSSHYFASKTRNERKRKK MP ASQRSKRRKT AS SGSKAKGGS ATCRKIS SKTKS S SIIGS SS ASHTSQ ATSGANS KLGIMAPPKPINRPFLKPSYAFS

Human BLM cDNA Sequence, Variant 3 (SEQ ID NO: 40)

ATGGAGCACATCTGTAAATTAATTGATACTATTCCTGATGATAAACTGAAACT TTTGGATTGTGGGAACGAACTGCTTCAGCAGCGGAACATAAGAAGGAAACTT CTAACGGAAGTAGATTTTAATAAAAGTGATGCCAGTCTTCTTGGCTCATTGTG GAGATACAGGCCTGATTCACTTGATGGCCCTATGGAGGGTGATTCCTGCCCTA CAGGGAATTCTATGAAGGAGTTAAATTTTTCACACCTTCCCTCAAATTCTGTT TCTCCTGGGGACTGTTTACTGACTACCACCCTAGGAAAGACAGGATTCTCTGC CACCAGGAAGAATCTTTTTGAAAGGCCTTTATTCAATACCCATTTACAGAAGT CCTTTGTAAGTAGCAACTGGGCTGAAACACCAAGACTAGGAAAAAAAAATG

AAAGCTCTTATTTCCCAGGAAATGTTCTCACAAGCACTGCTGTGAAAGATCA GAATAAACATACTGCTTCAATAAATGACTTAGAAAGAGAAACCCAACCTTCC

TATGATATTGATAATTTTGACATAGATGACTTTGATGATGATGATGACTGGGA AGACATAATGCATAATTTAGCAGCCAGCAAATCTTCCACAGCTGCCTATCAA CCCATCAAGGAAGGTCGGCCAATTAAATCAGTATCAGAAAGACTTTCCTCAG CCAAGACAGACTGTCTTCCAGTGTCATCTACTGCTCAAAATATAAACTTCTCA

GAGTCAATTCAGAATTATACTGACAAGTCAGCACAAAATTTAGCATCCAGAA

ATCTGAAACATGAGCGTTTCCAAAGTCTTAGTTTTCCTCATACAAAGGAAATG

ATGAAGATTTTTCATAAAAAATTTGGCCTGCATAATTTTAGAACTAATCAGCT

AGAGGCGATCAATGCTGCACTGCTTGGTGAAGACTGTTTTATCCTGATGCCGA

CTGGAGGTGGTAAGAGTTTGTGTTACCAGCTCCCTGCCTGTGTTTCTCCTGGG

GTCACTGTTGTCATTTCTCCCTTGAGATCACTTATCGTAGATCAAGTCCAAAA

GCTGACTTCCTTGGATATTCCAGCTACATATCTGACAGGTGATAAGACTGACT

CAGAAGCTACAAATATTTACCTCCAGTTATCAAAAAAAGACCCAATCATAAA

ACTTCTATATGTCACTCCAGAAAAGATCTGTGCAAGTAACAGACTCATTTCTA

CTCTGGAGAATCTCTATGAGAGGAAGCTCTTGGCACGTTTTGTTATTGATGAA

GCACATTGTGTCAGTCAGTGGGGACATGATTTTCGTCAAGATTACAAAAGAA

TGAATATGCTTCGCCAGAAGTTTCCTTCTGTTCCGGTGATGGCTCTTACGGCC

ACAGCTAATCCCAGGGTACAGAAGGACATCCTGACTCAGCTGAAGATTCTCA

GACCTCAGGTGTTTAGCATGAGCTTTAACAGACATAATCTGAAATACTATGTA

TTACCGAAAAAGCCTAAAAAGGTGGCATTTGATTGCCTAGAATGGATCAGAA

AGCACCACCCATATGATTCAGGGATAATTTACTGCCTCTCCAGGCGAGAATG

TGACACCATGGCTGACACGTTACAGAGAGATGGGCTCGCTGCTCTTGCTTACC

ATGCTGGCCTCAGTGATTCTGCCAGAGATGAAGTGCAGCAGAAGTGGATTAA

TCAGGATGGCTGTCAGGTTATCTGTGCTACAATTGCATTTGGAATGGGGATTG

ACAAACCGGACGTGCGATTTGTGATTCATGCATCTCTCCCTAAATCTGTGGAG

GGTTACTACCAAGAATCTGGCAGAGCTGGAAGAGATGGGGAAATATCTCACT

GCCTGCTTTTCTATACCTATCATGATGTGACCAGACTGAAAAGACTTATAATG

ATGGAAAAAGATGGAAACCATCATACAAGAGAAACTCACTTCAATAATTTGT

ATAGCATGGTACATTACTGTGAAAATATAACGGAATGCAGGAGAATACAGCT

TTTGGCCTACTTTGGTGAAAATGGATTTAATCCTGATTTTTGTAAGAAACACC

CAGATGTTTCTTGTGATAATTGCTGTAAAACAAAGGATTATAAAACAAGAGA

TGTGACTGACGATGTGAAAAGTATTGTAAGATTTGTTCAAGAACATAGTTCAT

CACAAGGAATGAGAAATATAAAACATGTAGGTCCTTCTGGAAGATTTACTAT

GAATATGCTGGTCGACATTTTCTTGGGGAGTAAGAGTGCAAAAATCCAGTCA

GGTATATTTGGAAAAGGATCTGCTTATTCACGACACAATGCCGAAAGACTTTT

TAAAAAGCTGATACTTGACAAGATTTTGGATGAAGACTTATATATCAATGCC

AATGACCAGGCGATCGCTTATGTGATGCTCGGAAATAAAGCCCAAACTGTAC

TAAATGGCAATTTAAAGGTAGACTTTATGGAAACAGAAAATTCCAGCAGTGT

GAAAAAACAAAAAGCGTTAGTAGCAAAAGTGTCTCAGAGGGAAGAGATGGT

TAAAAAATGTCTTGGAGAACTTACAGAAGTCTGCAAATCTCTGGGGAAAGT

TTTTGGTGTCCATTACTTCAATATTTTTAATACCGTCACTCTCAAGAAGCTTGC

AGAATCTTTATCTTCTGATCCTGAGGTTTTGCTTCAAATTGATGGTGTTACTGA

AGACAAACTGGAAAAATATGGTGCGGAAGTGATTTCAGTATTACAGAAATAC

TCTGAATGGACATCGCCAGCTGAAGACAGTTCCCCAGGGATAAGCCTGTCCA

GCAGCAGAGGCCCCGGAAGAAGTGCCGCTGAGGAGCTCGACGAGGAAATAC

CCGTATCTTCCCACTACTTTGCAAGTAAAACCAGAAATGAAAGGAAGAGGAA

AAAGATGCCAGCCTCCCAAAGGTCTAAGAGGAGAAAAACTGCTTCCAGTGGT

TCCAAGGCAAAGGGGGGGTCTGCCACATGTAGAAAGATATCTTCCAAAACGA

AATCCTCCAGCATCATTGGATCCAGTTCAGCCTCACATACTTCTCAAGCGACA TCAGGAGCCAATAGCAAATTGGGGATTATGGCTCCACCGAAGCCTATAAATA

GACCGTTTCTTAAGCCTTCATATGCATTCTCATAA

Human BLM Protein Sequence, Variant 3 (SEQ ID NO: 41)

MEHICKLIDTIPDDKLKLLDCGNELLQQRNIRRKLLTEVDFNKSDASLLGSLWRY RPDSLDGPMEGDSCPTGNSMKELNFSHLPSNSVSPGDCLLTTTLGKTGFSATRKN LFERPLFNTHLQKSFVSSNWAETPRLGKKNESSYFPGNVLTSTAVKDQNKHTASI NDLERETQPSYDIDNFDIDDFDDDDDWEDIMHNLAASKSSTAAYQPIKEGRPIKS VSERLSSAKTDCLPVSSTAQNINFSESIQNYTDKSAQNLASRNLKHERFQSLSFPH

TKEMMKIFHKKFGLHNFRTNQLEAINAALLGEDCFILMPTGGGKSLCYQLPACV SPGVTVVISPLRSLIVDQVQKLTSLDIPATYLTGDKTDSEATNIYLQLSKKDPIIKL LYVTPEKICASNRLISTLENLYERKLLARFVIDEAHCVSQWGHDFRQDYKRMNM LRQKFPSVPVMALTATANPRVQKDILTQLKILRPQVFSMSFNRHNLKYYVLPKKP KKVAFDCLEWIRKHHPYDSGIIYCLSRRECDTMADTLQRDGLAALAYHAGLSDS

ARDEVQQKWINQDGCQVICATIAFGMGIDKPDVRFVIHASLPKSVEGYYQESGR AGRDGEISHCLLFYTYHDVTRLKRLIMMEKDGNHHTRETHFNNLYSMVHYCENI TECRRIQLLAYFGENGFNPDFCKKHPDVSCDNCCKTKDYKTRDVTDDVKSIVRF VQEHSSSQGMRNIKHVGPSGRFTMNMLVDIFLGSKSAKIQSGIFGKGSAYSRHNA

ERLFKKLILDKILDEDLYINANDQAIAYVMLGNKAQTVLNGNLKVDFMETENSS SVKKQKALVAKVSQREEMVKKCLGELTEVCKSLGKVFGVHYFNIFNTVTLKKL AESL S SDPEVLLQIDGVTEDKLEK YGAE VIS VLQK YSEWTSP AED S SPGISL S S SR GPGRSAAEELDEEIPVSSHYFASKTRNERKRKKMPASQRSKRRKTASSGSKAKG GS ATCRKIS SKTKS S SIIGS SS ASHTSQ ATSGANSKLGIMAPPKPINRPFLKPS YAF S

Human PARP1 cDNA sequence (SEQ ID NO: 42)

ATGGCGGAGTCTTCGGATAAGCTCTATCGAGTCGAGTACGCCAAGAGCGGGC GCGCCTCTTGCAAGAAATGCAGCGAGAGCATCCCCAAGGACTCGCTCCGGAT GGCCATCATGGTGCAGTCGCCCATGTTTGATGGAAAAGTCCCACACTGGTAC CACTTCTCCTGCTTCTGGAAGGTGGGCCACTCCATCCGGCACCCTGACGTTGA GGTGGATGGGTTCTCTGAGCTTCGGTGGGATGACCAGCAGAAAGTCAAGAAG

ACAGCGGAAGCTGGAGGAGTGACAGGCAAAGGCCAGGATGGAATTGGTAGC AAGGCAGAGAAGACTCTGGGTGACTTTGCAGCAGAGTATGCCAAGTCCAACA GAAGTACGTGCAAGGGGTGTATGGAGAAGATAGAAAAGGGCCAGGTGCGCC TGTCCAAGAAGATGGTGGACCCGGAGAAGCCACAGCTAGGCATGATTGACCG CTGGTACCATCCAGGCTGCTTTGTCAAGAACAGGGAGGAGCTGGGTTTCCGG

CCCGAGTACAGTGCGAGTCAGCTCAAGGGCTTCAGCCTCCTTGCTACAGAGG ATAAAGAAGCCCTGAAGAAGCAGCTCCCAGGAGTCAAGAGTGAAGGAAAGA GAAAAGGCGATGAGGTGGATGGAGTGGATGAAGTGGCGAAGAAGAAATCTA AAAAAGAAAAAGACAAGGATAGTAAGCTTGAAAAAGCCCTAAAGGCTCAGA ACGACCTGATCTGGAACATCAAGGACGAGCTAAAGAAAGTGTGTTCAACTAA

TGACCTGAAGGAGCTACTCATCTTCAACAAGCAGCAAGTGCCTTCTGGGGAG TCGGCGATCTTGGACCGAGTAGCTGATGGCATGGTGTTCGGTGCCCTCCTTCC CTGCGAGGAATGCTCGGGTCAGCTGGTCTTCAAGAGCGATGCCTATTACTGC ACTGGGGACGTCACTGCCTGGACCAAGTGTATGGTCAAGACACAGACACCCA ACCGGAAGGAGTGGGTAACCCCAAAGGAATTCCGAGAAATCTCTTACCTCAA GAAATTGAAGGTTAAAAAACAGGACCGTATATTCCCCCCAGAAACCAGCGCC TCCGTGGCGGCCACGCCTCCGCCCTCCACAGCCTCGGCTCCTGCTGCTGTGAA CTCCTCTGCTTCAGCAGATAAGCCATTATCCAACATGAAGATCCTGACTCTCG GGAAGCTGTCCCGGAACAAGGATGAAGTGAAGGCCATGATTGAGAAACTCG GGGGGAAGTTGACGGGGACGGCCAACAAGGCTTCCCTGTGCATCAGCACCA AAAAGGAGGTGGAAAAGATGAATAAGAAGATGGAGGAAGTAAAGGAAGCC AACATCCGAGTTGTGTCTGAGGACTTCCTCCAGGACGTCTCCGCCTCCACCAA GAGCCTTCAGGAGTTGTTCTTAGCGCACATCTTGTCCCCTTGGGGGGCAGAGG TGAAGGCAGAGCCTGTTGAAGTTGTGGCCCCAAGAGGGAAGTCAGGGGCTGC GCTCTCCAAAAAAAGCAAGGGCCAGGTCAAGGAGGAAGGTATCAACAAATC TGAAAAGAGAATGAAATTAACTCTTAAAGGAGGAGCAGCTGTGGATCCTGAT TCTGGACTGGAACACTCTGCGCATGTCCTGGAGAAAGGTGGGAAGGTCTTCA GTGCCACCCTTGGCCTGGTGGACATCGTTAAAGGAACCAACTCCTACTACAA GCTGCAGCTTCTGGAGGACGACAAGGAAAACAGGTATTGGATATTCAGGTCC TGGGGCCGTGTGGGTACGGTGATCGGTAGCAACAAACTGGAACAGATGCCGT CCAAGGAGGATGCCATTGAGCACTTCATGAAATTATATGAAGAAAAAACCGG GAACGCTTGGCACTCCAAAAATTTCACGAAGTATCCCAAAAAGTTCTACCCC CTGGAGATTGACTATGGCCAGGATGAAGAGGCAGTGAAGAAGCTGACAGTA AATCCTGGCACCAAGTCCAAGCTCCCCAAGCCAGTTCAGGACCTCATCAAGA TGATCTTTGATGTGGAAAGTATGAAGAAAGCCATGGTGGAGTATGAGATCGA

CCTTCAGAAGATGCCCTTGGGGAAGCTGAGCAAAAGGCAGATCCAGGCCGC ATACTCCATCCTCAGTGAGGTCCAGCAGGCGGTGTCTCAGGGCAGCAGCGAC TCTCAGATCCTGGATCTCTCAAATCGCTTTTACACCCTGATCCCCCACGACTT TGGGATGAAGAAGCCTCCGCTCCTGAACAATGCAGACAGTGTGCAGGCCAAG GTGGAAATGCTTGACAACCTGCTGGACATCGAGGTGGCCTACAGTCTGCTCA GGGGAGGGTCTGATGATAGCAGCAAGGATCCCATCGATGTCAACTATGAGAA GCTCAAAACTGACATTAAGGTGGTTGACAGAGATTCTGAAGAAGCCGAGATC ATCAGGAAGTATGTTAAGAACACTCATGCAACCACACACAATGCGTATGACT TGGAAGTCATCGATATCTTTAAGATAGAGCGTGAAGGCGAATGCCAGCGTTA CAAGCCCTTTAAGCAGCTTCATAACCGAAGATTGCTGTGGCACGGGTCCAGG ACCACCAACTTTGCTGGGATCCTGTCCCAGGGTCTTCGGATAGCCCCGCCTGA AGCGCCCGTGACAGGCTACATGTTTGGTAAAGGGATCTATTTCGCTGACATG GTCTCCAAGAGTGCCAACTACTGCCATACGTCTCAGGGAGACCCAATAGGCT TAATCCTGTTGGGAGAAGTTGCCCTTGGAAACATGTATGAACTGAAGCACGC TTCACATATCAGCAAGTTACCCAAGGGCAAGCACAGTGTCAAAGGTTTGGGC AAAACTACCCCTGATCCTTCAGCTAACATTAGTCTGGATGGTGTAGACGTTCC TCTTGGGACCGGGATTTCATCTGGTGTGAATGACACCTCTCTACTATATAACG AGTACATTGTCTATGATATTGCTCAGGTAAATCTGAAGTATCTGCTGAAACTG AAATTCAATTTTAAGACCTCCCTGTGGTAA Human PARP protein sequence (SEQ ID NO: 43)

MAES SDKLYRVEYAKSGRASCKKC SESIPKD SLRMAIMVQSPMFDGKVPHWYH F SCFWKVGHSIRHPDVEVDGF SELRWDDQQKVKKTAEAGGVTGKGQDGIGSKA EKTLGDFAAEYAKSNRSTCKGCMEKIEKGQVRLSKKMVDPEKPQLGMIDRWYH PGCFVKNREELGFRPEYSASQLKGFSLLATEDKEALKKQLPGVKSEGKRKGDEV DGVDEVAKKKSKKEKDKDSKLEKALKAQNDLIWNIKDELKKVCSTNDLKELLIF NKQQVPSGESAILDRVADGMVFGALLPCEECSGQLVFKSDAYYCTGDVTAWTK CMVKTQTPNRKEWVTPKEFREISYLKKLKVKKQDRIFPPETSASVAATPPPSTAS APAAVNSSASADKPLSNMKILTLGKLSRNKDEVKAMIEKLGGKLTGTANKASLC ISTKKEVEKMNKKMEEVKEANIRVVSEDFLQDVSASTKSLQELFLAHILSPWGAE VKAEPVEVVAPRGKSGAALSKKSKGQVKEEGINKSEKRMKLTLKGGAAVDPDS GLEHSAHVLEKGGKVFSATLGLVDIVKGTNSYYKLQLLEDDKENRYWIFRSWG RVGTVIGSNKLEQMPSKEDAIEHFMKLYEEKTGNAWHSKNFTKYPKKFYPLEID YGQDEEAVKKLTVNPGTKSKLPKPVQDLIKMIFDVESMKKAMVEYEIDLQKMPL GKLSKRQIQAAYSILSEVQQAVSQGSSDSQILDLSNRFYTLIPHDFGMKKPPLLNN ADSVQAKVEMLDNLLDIEVAYSLLRGGSDDSSKDPIDVNYEKLKTDIKVVDRDS EEAEIIRKYVKNTHATTHNAYDLEVIDIFKIEREGECQRYKPFKQLHNRRLLWHG SRTTNFAGILSQGLRIAPPEAPVTGYMFGKGIYFADMVSKSANYCHTSQGDPIGLI LLGEVALGNMYELKHASHISKLPKGKHSVKGLGKTTPDPSANISLDGVDVPLGT GISSGVNDTSLLYNEYIVYDIAQVNLKYLLKLKFNFKTSLW

Human RPA1 cDNA Sequence, Variant 1 (SEQ ID NO: 44)

ATGGTCGGCCAACTGAGCGAGGGGGCCATTGCGGCCATCATGCAGAAGGGG GATACAAACATAAAGCCCATCCTCCAAGTCATCAACATCCGTCCCATTACTA CGGGGAATAGTCCGCCGCGTTATCGACTGCTCATGAGTGATGGATTGAACAC TCTATCCTCTTTCATGTTGGCGACACAGTTGAACCCTCTCGTGGAGGAAGAAC AATTGTCCAGCAACTGTGTATGCCAGATTCACAGATTTATTGTGAACACTCTG AAAGACGGAAGGAGAGTAGTTATCTTGATGGAATTAGAAGTTTTGAAGTCAG CTGAAGCAGTTGGAGTGAAGATTGGCAATCCAGTGCCCTATAATGAAGGACT CGGGCAGCCGCAAGTAGCTCCTCCAGCGCCAGCAGCCAGCCCAGCAGCAAG CAGCAGGCCCCAGCCGCAGAATGGAAGCTCGGGAATGGGTTCTACTGTTTCT AAGGCTTATGGTGCTTCAAAGACATTTGGAAAAGCTGCAGGTCCCAGCCTGT CACACACTTCTGGGGGAACACAGTCCAAAGTGGTGCCCATTGCCAGCCTCAC TCCTTACCAGTCCAAGTGGACCATTTGTGCTCGTGTTACCAACAAAAGTCAGA TCCGTACCTGGAGCAACTCCCGAGGGGAAGGGAAGCTTTTCTCCCTAGAACT GGTTGACGAAAGTGGTGAAATCCGAGCTACAGCTTTCAATGAGCAAGTGGAC AAGTTCTTTCCTCTTATTGAAGTGAACAAGGTGTATTATTTCTCGAAAGGCAC CCTGAAGATTGCTAACAAGCAGTTCACAGCTGTTAAAAATGACTACGAGATG ACCTTCAATAACGAGACTTCCGTCATGCCCTGTGAGGACGACCATCATTTACC TACGGTTCAGTTTGATTTCACGGGGATTGATGACCTCGAGAACAAGTCGAAA GACTCACTTGTAGACATCATCGGGATCTGCAAGAGCTATGAAGACGCCACTA AAATCACAGTGAGGTCTAACAACAGAGAAGTTGCCAAGAGGAATATCTACTT GATGGACACATCCGGGAAGGTGGTGACTGCTACACTGTGGGGGGAAGATGCT GATAAATTTGATGGTTCTAGACAGCCCGTGTTGGCTATCAAAGGAGCCCGAG TCTCTGATTTCGGTGGACGGAGCCTCTCCGTGCTGTCTTCAAGCACTATCATT GCGAATCCTGACATCCCAGAGGCCTATAAGCTTCGTGGATGGTTTGACGCAG AAGGACAAGCCTTAGATGGTGTTTCCATCTCTGATCTAAAGAGCGGCGGAGT CGGAGGGAGTAACACCAACTGGAAAACCTTGTATGAGGTCAAATCCGAGAA CCTGGGCCAAGGCGACAAGCCGGACTACTTTAGTTCTGTGGCCACAGTGGTG TATCTTCGCAAAGAGAACTGCATGTACCAAGCCTGCCCGACTCAGGACTGCA ATAAGAAAGTGATTGATCAACAGAATGGATTGTACCGCTGTGAGAAGTGCGA

CACCGAATTTCCCAATTTCAAGTACCGCATGATCCTGTCAGTAAATATTGCAG ATTTTCAAGAGAATCAGTGGGTGACTTGTTTCCAGGAGTCTGCTGAAGCTATC CTTGGACAAAATGCTGCTTATCTTGGGGAATTAAAAGACAAGAATGAACAGG CATTTGAAGAAGTTTTCCAGAATGCCAACTTCCGATCTTTCATATTCAGAGTC AGGGTCAAAGTGGAGACCTACAACGACGAGTCTCGAATTAAGGCCACTGTGA TGGACGTGAAGCCCGTGGACTACAGAGAGTATGGCCGAAGGCTGGTCATGAG CATCAGGAGAAGTGCATTGATGTGA

Human RPA1 Protein Sequence, Variant 1 (SEQ ID NO: 45)

MVGQLSEGAIAAIMQKGDTNIKPILQVINIRPITTGNSPPRYRLLMSDGLNTLSSF MLATQLNPLVEEEQLSSNCVCQIHRFIVNTLKDGRRVVILMELEVLKSAEAVGVK IGNPVPYNEGLGQPQVAPPAPAASPAASSRPQPQNGSSGMGSTVSKAYGASKTF GKAAGPSLSHTSGGTQSKVVPIASLTPYQSKWTICARVTNKSQIRTWSNSRGEGK LFSLELVDESGEIRATAFNEQVDKFFPLIEVNKVYYFSKGTLKIANKQFTAVKND YEMTFNNETSVMPCEDDHHLPTVQFDFTGIDDLENKSKDSLVDIIGICKSYEDAT KITVRSNNREVAKRNIYLMDTSGKVVTATLWGEDADKFDGSRQPVLAIKGARVS DFGGRSLSVLSSSTIIANPDIPEAYKLRGWFDAEGQALDGVSISDLKSGGVGGSNT

NWKTLYEVKSENLGQGDKPDYFSSVATVVYLRKENCMYQACPTQDCNKKVID QQNGLYRCEKCDTEFPNFKYRMILSVNIADFQENQWVTCFQESAEAILGQNAAY

LGELKDKNEQAFEEVFQNANFRSFIFRVRVKVETYNDESRIKATVMDVKPVDYR EYGRRLVMSIRRSALM

Human RPA1 cDNA Sequence, Variant 2 (SEQ ID NO: 46)

ATGCAGAAGGGGGATACAAACATAAAGCCCATCCTCCAAGTCATCAACATCC GTCCCATTACTACGGGGAATAGTCCGCCGCGTTATCGACTGCTCATGAGTGAT GGATTGAACACTCTATCCTCTTTCATGTTGGCGACACAGTTGAACCCTCTCGT GGAGGAAGAACAATTGTCCAGCAACTGTGTATGCCAGATTCACAGATTTATT GTGAACACTCTGAAAGACGGAAGGAGAGTAGTTATCTTGATGGAATTAGAAG TTTTGAAGTCAGCTGAAGCAGTTGGAGTGAAGATTGGCAATCCAGTGCCCTA TAATGAAGGACTCGGGCAGCCGCAAGTAGCTCCTCCAGCGCCAGCAGCCAGC CCAGCAGCAAGCAGCAGGCCCCAGCCGCAGAATGGAAGCTCGGGAATGGGT

TCTACTGTTTCTAAGGCTTATGGTGCTTCAAAGACATTTGGAAAAGCTGCAGG TCCCAGCCTGTCACACACTTCTGGGGGAACACAGTCCAAAGTGGTGCCCATT GCCAGCCTCACTCCTTACCAGTCCAAGTGGACCATTTGTGCTCGTGTTACCAA CAAAAGTCAGATCCGTACCTGGAGCAACTCCCGAGGGGAAGGGAAGCTTTTC TCCCTAGAACTGGTTGACGAAAGTGGTGAAATCCGAGCTACAGCTTTCAATG AGCAAGTGGACAAGTTCTTTCCTCTTATTGAAGTGAACAAGGTGTATTATTTC TCGAAAGGCACCCTGAAGATTGCTAACAAGCAGTTCACAGCTGTTAAAAATG ACTACGAGATGACCTTCAATAACGAGACTTCCGTCATGCCCTGTGAGGACGA CCATCATTTACCTACGGTTCAGTTTGATTTCACGGGGATTGATGACCTCGAGA ACAAGTCGAAAGACTCACTTGTAGACATCATCGGGATCTGCAAGAGCTATGA AGACGCCACTAAAATCACAGTGAGGTCTAACAACAGAGAAGTTGCCAAGAG GAATATCTACTTGATGGACACATCCGGGAAGGTGGTGACTGCTACACTGTGG GGGGAAGATGCTGATAAATTTGATGGTTCTAGACAGCCCGTGTTGGCTATCA AAGGAGCCCGAGTCTCTGATTTCGGTGGACGGAGCCTCTCCGTGCTGTCTTCA AGCACTATCATTGCGAATCCTGACATCCCAGAGGCCTATAAGCTTCGTGGAT GGTTTGACGCAGAAGGACAAGCCTTAGATGGTGTTTCCATCTCTGATCTAAA GAGCGGCGGAGTCGGAGGGAGTAACACCAACTGGAAAACCTTGTATGAGGT

CAAATCCGAGAACCTGGGCCAAGGCGACAAGCCGGACTACTTTAGTTCTGTG GCCACAGTGGTGTATCTTCGCAAAGAGAACTGCATGTACCAAGCCTGCCCGA CTCAGGACTGCAATAAGAAAGTGATTGATCAACAGAATGGATTGTACCGCTG TGAGAAGTGCGACACCGAATTTCCCAATTTCAAGTACCGCATGATCCTGTCA GTAAATATTGCAGATTTTCAAGAGAATCAGTGGGTGACTTGTTTCCAGGAGTC TGCTGAAGCTATCCTTGGACAAAATGCTGCTTATCTTGGGGAATTAAAAGAC AAGAATGAACAGGCATTTGAAGAAGTTTTCCAGAATGCCAACTTCCGATCTT

TCATATTCAGAGTCAGGGTCAAAGTGGAGACCTACAACGACGAGTCTCGAAT TAAGGCCACTGTGATGGACGTGAAGCCCGTGGACTACAGAGAGTATGGCCGA AGGCTGGTCATGAGCATCAGGAGAAGTGCATTGATGTGA

Human RPA1 Protein Sequence, Variant 2 (SEQ ID NO: 47)

MQKGDTNIKPILQVINIRPITTGNSPPRYRLLMSDGLNTLSSFMLATQLNPLVEEE QLSSNCVCQIHRFIVNTLKDGRRVVILMELEVLKSAEAVGVKIGNPVPYNEGLGQ PQVAPPAPAASPAASSRPQPQNGSSGMGSTVSKAYGASKTFGKAAGPSLSHTSG GTQSKVVPIASLTPYQSKWTICARVTNKSQIRTWSNSRGEGKLFSLELVDESGEIR ATAFNEQVDKFFPLIEVNKVYYFSKGTLKIANKQFTAVKNDYEMTFNNETSVMP CEDDHHLPTVQFDFTGIDDLENKSKDSLVDIIGICKSYEDATKITVRSNNREVAKR NIYLMDTSGKVVTATLWGEDADKFDGSRQPVLAIKGARVSDFGGRSLSVLSSSTI

IANPDIPEAYKLRGWFDAEGQALDGVSISDLKSGGVGGSNTNWKTLYEVKSENL GQGDKPD YF S S VAT VVYLRKENCM YQ ACPTQDCNKK VIDQQNGLYRCEKCDTE FPNFKYRMILSVNIADFQENQWVTCFQESAEAILGQNAAYLGELKDKNEQAFEE VFQNANFRSFIFRVRVKVETYNDESRIKATVMDVKPVDYREYGRRLVMSIRRSA LM

Human RPA1 cDNA Sequence, Variant 3 (SEQ ID NO: 48)

ATGGTCGGCCAACTGAGCGAGGGGGCCATTGCGGCCATCATGCAGAAGGGG GATACAAACATAAAGCCCATCCTCCAAGTCATCAACATCCGTCCCATTACTA CGGGGAATAGTCCGCCGCGTTATCGACTGCTCATGAGTGATGGATTGAACAC TCTATCCTCTTTCATGTTGGCGACACAGTTGAACCCTCTCGTGGAGGAAGAAC AATTGTCCAGCAACTGTGTATGCCAGATTCACAGATTTATTGTGAACACTCTG AAAGACGGAAGGAGAGTAGTTATCTTGATGGAATTAGAAGTTTTGAAGTCAG CTGAAGCAGTTGGAGTGAAGATTGGCAATCCAGTGCCCTATAATGAAGGACT CGGGCAGCCGCAAGTAGCTCCTCCAGCGCCAGCAGCCAGCCCAGCAGCAAG CAGCAGGCCCCAGCCGCAGAATGGAAGCTCGGGAATGGGTTCTACTGTTTCT AAGGCTTATGGTGCTTCAAAGACATTTGGAAAAGCTGCAGGTCCCAGCCTGT CACACACTTCTGGGGGAACACAGTCCAAAGTGGTGCCCATTGCCAGCCTCAC TCCTTACCAGTCCAAGTGGACCATTTGTGCTCGTGTTACCAACAAAAGTCAGA TCCGTACCTGGAGCAACTCCCGAGGGGAAGGGAAGCTTTTCTCCCTAGAACT GGTTGACGAAAGTGGTGAAATCCGAGCTACAGCTTTCAATGAGCAAGTGGAC AAGTTCTTTCCTCTTATTGAAGTGAACAAGGTGTATTATTTCTCGAAAGGCAC CCTGAAGATTGCTAACAAGCAGTTCACAGCTGTTAAAAATGACTACGAGATG ACCTTCAATAACGAGACTTCCGTCATGCCCTGTGAGGACGACCATCATTTACC TACGGTTCAGTTTGATTTCACGGGGATTGATGACCTCGAGAACAAGTCGAAA GACTCACTTGTAGACATCATCGGGATCTGCAAGAGCTATGAAGACGCCACTA AAATCACAGTGAGGTCTAACAACAGAGAAGTTGCCAAGAGGAATATCTACTT GATGGACACATCCGGGAAGGTGGTGACTGCTACACTGTGGGGGGAAGATGCT GATAAATTTGATGGTTCTAGACAGCCCGTGTTGGCTATCAAAGGAGCCCGAG TCTCTGATTTCGGTGGACGGAGCCTCTCCGTGCTGTCTTCAAGCACTATCATT GCGAATCCTGACATCCCAGAGGCCTATAAGCTTCGTGGATGGTTTGACGCAG AAGGACAAGCCTTAGATGGTGTTTCCATCTCTGATCTAAAGAGCGGCGGAGT CGGAGGGAGTAACACCAACTGGAAAACCTTGTATGAGGTCAAATCCGAGAA CCTGGGCCAAGGCGACAAGGTAAATATTGCAGATTTTCAAGAGAATCAGTGG GTGACTTGTTTCCAGGAGTCTGCTGAAGCTATCCTTGGACAAAATGCTGCTTA TCTTGGGGAATTAAAAGACAAGAATGAACAGGCATTTGAAGAAGTTTTCCAG AATGCCAACTTCCGATCTTTCATATTCAGAGTCAGGGTCAAAGTGGAGACCT ACAACGACGAGTCTCGAATTAAGGCCACTGTGATGGACGTGAAGCCCGTGGA CTACAGAGAGTATGGCCGAAGGCTGGTCATGAGCATCAGGAGAAGTGCATTG ATGTGA

Human RPA1 Protein Sequence, Variant 3 (SEQ ID NO: 49)

MVGQLSEGAIAAIMQKGDTNIKPILQVINIRPITTGNSPPRYRLLMSDGLNTLSSF MLATQLNPLVEEEQLSSNCVCQIHRFIVNTLKDGRRVVILMELEVLKSAEAVGVK IGNPVPYNEGLGQPQ VAPP AP AASPAAS SRPQPQNGS SGMGST VSKAYGASKTF GKAAGPSLSHTSGGTQSKVVPIASLTPYQSKWTICARVTNKSQIRTWSNSRGEGK LFSLELVDESGEIRATAFNEQVDKFFPLIEVNKVYYFSKGTLKIANKQFTAVKND YEMTFNNETSVMPCEDDHHLPTVQFDFTGIDDLENKSKDSLVDIIGICKSYEDAT KITVRSNNREVAKRNIYLMDTSGKVVTATLWGEDADKFDGSRQPVLAIKGARVS DFGGRSLSVLSSSTIIANPDIPEAYKLRGWFDAEGQALDGVSISDLKSGGVGGSNT NWKTLYEVKSENLGQGDKVNIADFQENQWVTCFQESAEAILGQNAAYLGELKD KNEQAFEEVFQNANFRSFIFRVRVKVETYNDESRIKATVMDVKPVDYREYGRRL VMSIRRSALM Human RAD51 cDNA Sequence, Variant 1 (SEQ ID NO: 50)

ATGGCAATGCAGATGCAGCTTGAAGCAAATGCAGATACTTCAGTGGAAGAAG AAAGCTTTGGCCCACAACCCATTTCACGGTTAGAGCAGTGTGGCATAAATGC CAACGATGTGAAGAAATTGGAAGAAGCTGGATTCCATACTGTGGAGGCTGTT GCCTATGCGCCAAAGAAGGAGCTAATAAATATTAAGGGAATTAGTGAAGCCA AAGCTGATAAAATTCTGGCTGAGGCAGCTAAATTAGTTCCAATGGGTTTCAC CACTGCAACTGAATTCCACCAAAGGCGGTCAGAGATCATACAGATTACTACT

GGCTCCAAAGAGCTTGACAAACTACTTCAAGGTGGAATTGAGACTGGATCTA TCACAGAAATGTTTGGAGAATTCCGAACTGGGAAGACCCAGATCTGTCATAC GCTAGCTGTCACCTGCCAGCTTCCCATTGACCGGGGTGGAGGTGAAGGAAAG GCCATGTACATTGACACTGAGGGTACCTTTAGGCCAGAACGGCTGCTGGCAG

TGGCTGAGAGGTATGGTCTCTCTGGCAGTGATGTCCTGGATAATGTAGCATAT

GCTCGAGCGTTCAACACAGACCACCAGACCCAGCTCCTTTATCAAGCATCAG CCATGATGGTAGAATCTAGGTATGCACTGCTTATTGTAGACAGTGCCACCGCC CTTTACAGAACAGACTACTCGGGTCGAGGTGAGCTTTCAGCCAGGCAGATGC ACTTGGCCAGGTTTCTGCGGATGCTTCTGCGACTCGCTGATGAGTTTGGTGTA

GCAGTGGTAATCACTAATCAGGTGGTAGCTCAAGTGGATGGAGCAGCGATGT TTGCTGCTGATCCCAAAAAACCTATTGGAGGAAATATCATCGCCCATGCATC AACAACCAGATTGTATCTGAGGAAAGGAAGAGGGGAAACCAGAATCTGCAA AATCTACGACTCTCCCTGTCTTCCTGAAGCTGAAGCTATGTTCGCCATTAATG

CAGATGGAGTGGGAGATGCCAAAGACTGA

Human RAD51 Protein Sequence, Variant 1 (SEQ ID NO: 51)

MAMQMQLEANADTSVEEESFGPQPISRLEQCGINANDVKKLEEAGFHTVEAVAY

APKKELINIKGISEAKADKILAEAAKLVPMGFTTATEFHQRRSEIIQITTGSKELDK

LLQGGIETGSITEMFGEFRTGKTQICHTLAVTCQLPIDRGGGEGKAMYIDTEGTFR

PERLLAVAERYGLSGSDVLDNVAYARAFNTDHQTQLLYQASAMMVESRYALLI

VDSATALYRTDYSGRGELSARQMHLARFLRMLLRLADEFGVAVVITNQVVAQV DGAAMFAADPKKPIGGNIIAHASTTRLYLRKGRGETRICKIYDSPCLPEAEAMFAI NADGVGDAKD

Human RAD51 cDNA Sequence, Variant 2 (SEQ ID NO: 52)

ATGGCAATGCAGATGCAGCTTGAAGCAAATGCAGATACTTCAGTGGAAGAAG AAAGCTTTGGCCCACAACCCATTTCACGGTTAGAGCAGTGTGGCATAAATGC CAACGATGTGAAGAAATTGGAAGAAGCTGGATTCCATACTGTGGAGGCTGTT GCCTATGCGCCAAAGAAGGAGCTAATAAATATTAAGGGAATTAGTGAAGCCA

AAGCTGATAAAATTCTGACGGAGTCTCGCTCTGTTGCCAGGCTGGAGTGCAA

TAGCGTGATCTTGGTCTACTGCACCCTCCGCCTCTCAGGTTCAAGTGATTCTC

CTGCCTCAGCCTCCCGAGTAGTTGGGACTACAGGTGGAATTGAGACTGGATC TATCACAGAAATGTTTGGAGAATTCCGAACTGGGAAGACCCAGATCTGTCAT ACGCTAGCTGTCACCTGCCAGCTTCCCATTGACCGGGGTGGAGGTGAAGGAA AGGCCATGTACATTGACACTGAGGGTACCTTTAGGCCAGAACGGCTGCTGGC AGTGGCTGAGAGGTATGGTCTCTCTGGCAGTGATGTCCTGGATAATGTAGCA TATGCTCGAGCGTTCAACACAGACCACCAGACCCAGCTCCTTTATCAAGCAT CAGCCATGATGGTAGAATCTAGGTATGCACTGCTTATTGTAGACAGTGCCAC CGCCCTTTACAGAACAGACTACTCGGGTCGAGGTGAGCTTTCAGCCAGGCAG ATGCACTTGGCCAGGTTTCTGCGGATGCTTCTGCGACTCGCTGATGAGTTTGG TGTAGCAGTGGTAATCACTAATCAGGTGGTAGCTCAAGTGGATGGAGCAGCG

ATGTTTGCTGCTGATCCCAAAAAACCTATTGGAGGAAATATCATCGCCCATGC ATCAACAACCAGATTGTATCTGAGGAAAGGAAGAGGGGAAACCAGAATCTG CAAAATCTACGACTCTCCCTGTCTTCCTGAAGCTGAAGCTATGTTCGCCATTA ATGCAGATGGAGTGGGAGATGCCAAAGACTGA

Human RAD51 Protein Sequence, Variant 2 (SEQ ID NO: 53)

MAMQMQLEANADTSVEEESFGPQPISRLEQCGINANDVKKLEEAGFHTVEAVAY APKKELINIKGISEAKADKILTESRSVARLECNSVILVYCTLRLSGSSDSPASASRV VGTTGGIETGSITEMFGEFRTGKTQICHTLAVTCQLPIDRGGGEGKAMYIDTEGTF RPERLLAVAERYGLSGSDVLDNVAYARAFNTDHQTQLLYQASAMMVESRYALL IVDSATALYRTDYSGRGELSARQMHLARFLRMLLRLADEFGVAVVITNQVVAQ VDGAAMFAADPKKPIGGNIIAHASTTRLYLRKGRGETRICKIYDSPCLPEAEAMF

AINADGVGDAKD

Human RAD51 cDNA Sequence, Variant 3 (SEQ ID NO: 54)

ATGGCAATGCAGATGCAGCTTGAAGCAAATGCAGATACTTCAGTGGAAGAAG AAAGCTTTGGCCCACAACCCATTTCACGGTTAGAGCAGTGTGGCATAAATGC CAACGATGTGAAGAAATTGGAAGAAGCTGGATTCCATACTGTGGAGGCTGTT GCCTATGCGCCAAAGAAGGAGCTAATAAATATTAAGGGAATTAGTGAAGCCA AAGCTGATAAAATTCTGGCTGAGGCAGCTAAATTAGTTCCAATGGGTTTCAC CACTGCAACTGAATTCCACCAAAGGCGGTCAGAGATCATACAGATTACTACT

GGCTCCAAAGAGCTTGACAAACTACTTCAAGGTGGAATTGAGACTGGATCTA TCACAGAAATGTTTGGAGAATTCCGAACTGGGAAGACCCAGATCTGTCATAC GCTAGCTGTCACCTGCCAGCTTCCCATTGACCGGGGTGGAGGTGAAGGAAAG GCCATGTACATTGACACTGAGGGTACCTTTAGGCCAGAACGGCTGCTGGCAG TGGCTGAGAGGTATGGTCTCTCTGGCAGTGATGTCCTGGATAATGTAGCATAT GCTCGAGCGTTCAACACAGACCACCAGACCCAGCTCCTTTATCAAGCATCAG

CCATGATGGTAGAATCTAGGTATGCACTGCTTATTGTAGACAGTGCCACCGCC CTTTACAGAACAGACTACTCGGGTCGAGGTGAGCTTTCAGCCAGGCAGATGC ACTTGGCCAGGTTTCTGCGGATGCTTCTGCGACTCGCTGATGAGATTGTATCT GAGGAAAGGAAGAGGGGAAACCAGAATCTGCAAAATCTACGACTCTCCCTG TCTTCCTGA

Human RAD51 Protein Sequence, Variant 3 (SEQ ID NO: 55)

MAMQMQLEANADTSVEEESFGPQPISRLEQCGINANDVKKLEEAGFHTVEAVAY

APKKELINIKGISEAKADKILAEAAKLVPMGFTTATEFHQRRSEIIQITTGSKELDK LLQGGIETGSITEMFGEFRTGKTQICHTLAVTCQLPIDRGGGEGKAMYIDTEGTFR PERLLAVAERYGLSGSDVLDNVAYARAFNTDHQTQLLYQASAMMVESRYALLI VDSATALYRTDYSGRGELSARQMHLARFLRMLLRLADEIVSEERKRGNQNLQN LRLSLSS

Human MUS81 cDNA Sequence, Variant 1 (SEQ ID NO: 56)

ATGGCGGCCCCGGTCCGCCTGGGCCGGAAGCGCCCGCTGCCTGCCTGTCCCA ACCCGCTCTTCGTTCGCTGGCTGACCGAGTGGCGGGACGAGGCGACCCGCAG CAGGCGCCGCACGCGCTTCGTATTTCAGAAGGCGCTGCGTTCCCTCCGACGG TACCCACTGCCGCTGCGCAGCGGGAAGGAAGCTAAGATCCTACAGCACTTCG GAGACGGGCTCTGCCGGATGCTGGACGAGCGGCTGCAGCGGCACCGAACAT CGGGCGGTGACCATGCCCCGGACTCACCATCTGGAGAGAACAGTCCAGCCCC GCAGGGGCGACTTGCGGAAGTCCAGGACTCTTCCATGCCAGTTCCTGCCCAG CCCAAAGCGGGAGGCTCTGGCAGCTACTGGCCAGCTCGGCACTCAGGAGCCC GAGTGATACTGCTGGTGCTCTACCGGGAGCACCTGAATCCTAATGGTCACCA CTTCTTAACCAAGGAGGAGCTGCTGCAGAGGTGTGCTCAGAAGTCCCCCAGG GTAGCCCCTGGGAGTGCTCGACCCTGGCCAGCCCTCCGCTCCCTCCTTCACAG GAACCTGGTCCTCAGGACACACCAGCCAGCCAGGTACTCATTGACCCCAGAG GGCCTGGAGCTGGCCCAGAAGTTGGCCGAGTCAGAAGGCCTGAGCTTGCTGA ATGTGGGCATCGGGCCCAAGGAGCCCCCTGGGGAGGAGACAGCAGTGCCAG GAGCAGCTTCAGCAGAGCTTGCCAGTGAAGCAGGGGTCCAGCAGCAGCCACT GGAGCTGAGGCCTGGAGAGTACAGGGTGCTGTTGTGTGTGGACATTGGCGAG ACCCGGGGGGGCGGGCACAGGCCGGAGCTGCTCCGAGAGCTACAGCGGCTG CACGTGACCCACACGGTGCGCAAGCTGCACGTTGGAGATTTTGTGTGGGTGG CCCAGGAGACCAATCCTAGAGACCCAGCAGCAAACCCTGGGGAGTTGGTACT GGATCACATTGTGGAGCGCAAGCGACTGGATGACCTTTGCAGCAGCATCATC GACGGCCGCTTCCGGGAGCAGAAGTTCCGGCTGAAGCGCTGTGGTCTGGAGC GCCGGGTATACCTGGTGGAAGAGCATGGTTCCGTCCACAACCTCAGCCTTCC TGAGAGCACACTGCTGCAGGCTGTCACCAACACTCAGGTCATTGATGGCTTTT

TTGTGAAGCGCACAGCAGACATTAAGGAGTCAGCCGCCTACCTGGCCCTCTT GACGCGGGGCCTGCAGAGACTCTACCAGGGCCACACCCTACGCAGCCGCCCC TGGGGAACCCCTGGGAACCCTGAATCAGGGGCCATGACCTCTCCAAACCCTC TCTGCTCACTCCTCACCTTCAGTGACTTCAACGCAGGAGCCATCAAGAATAA GGCCCAGTCGGTGCGAGAAGTGTTTGCCCGGCAGCTGATGCAGGTGCGCGGA GTGAGTGGGGAGAAGGCAGCAGCCCTGGTGGATCGATACAGCACCCCTGCC AGCCTCCTGGCCGCCTATGATGCCTGTGCCACCCCCAAGGAACAAGAGACAC TGCTGAGCACCATTAAGTGTGGGCGTCTACAGAGGAATCTGGGGCCTGCTCT GAGCAGGACCTTATCCCAGCTCTACTGCAGCTACGGCCCCTTGACCTGA

Human MUS81 Protein Sequence, Variant 1 (SEQ ID NO: 57)

MAAPVRLGRKRPLPACPNPLFVRWLTEWRDEATRSRRRTRFVFQKALRSLRRYP LPLRSGKEAKILQHFGDGLCRMLDERLQRHRTSGGDHAPDSPSGENSPAPQGRL AEVQDSSMPVPAQPKAGGSGSYWPARHSGARVILLVLYREHLNPNGHHFLTKEE LLQRCAQKSPRVAPGSARPWPALRSLLHRNLVLRTHQPARYSLTPEGLELAQKL AESEGLSLLNVGIGPKEPPGEETAVPGAASAELASEAGVQQQPLELRPGEYRVLL CVDIGETRGGGHRPELLRELQRLHVTHTVRKLHVGDFVWVAQETNPRDPAANP GELVLDHIVERKRLDDLCSSIIDGRFREQKFRLKRCGLERRVYLVEEHGSVHNLS LPESTLLQAVTNTQVIDGFFVKRTADIKESAAYLALLTRGLQRLYQGHTLRSRPW GTPGNPESGAMTSPNPLCSLLTFSDFNAGAIKNKAQSVREVFARQLMQVRGVSG EKAAALVDRYSTPASLLAAYDACATPKEQETLLSTIKCGRLQRNLGPALSRTLSQ LYCSYGPLT

Human MUS81 cDNA Sequence, Variant 2 (SEQ ID NO: 58)

ATGGCGGCCCCGGTCCGCCTGGGCCGGAAGCGCCCGCTGCCTGCCTGTCCCA ACCCGCTCTTCGTTCGCTGGCTGACCGAGTGGCGGGACGAGGCGACCCGCAG CAGGCGCCGCACGCGCTTCGTATTTCAGAAGGCGCTGCGTTCCCTCCGACGG TACCCACTGCCGCTGCGCAGCGGGAAGGAAGCTAAGATCCTACAGCACTTCG GAGACGGGCTCTGCCGGATGCTGGACGAGCGGCTGCAGCGGCACCGAACAT CGGGCGGTGACCATGCCCCGGACTCACCATCTGGAGAGAACAGTCCAGCCCC GCAGGGGCGACTTGCGGAAGTCCAGGACTCTTCCATGCCAGTTCCTGCCCAG CCCAAAGCGGGAGGCTCTGGCAGCTACTGGCCAGCTCGGCACTCAGGAGCCC GAGTGATACTGCTGGTGCTCTACCGGGAGCACCTGAATCCTAATGGTCACCA CTTCTTAACCAAGGAGGAGCTGCTGCAGAGGTGTGCTCAGAAGTCCCCCAGG GTAGCCCCTGGGAGTGCTCGACCCTGGCCAGCCCTCCGCTCCCTCCTTCACAG GAACCTGGTCCTCAGGACACACCAGCCAGCCAGGTACTCATTGACCCCAGAG GGCCTGGAGCTGGCCCAGAAGTTGGCCGAGTCAGAAGGCCTGAGCTTGCTGA ATGTGGGCATCGGGCCCAAGGAGCCCCCTGGGGAGGAGACAGCAGTGCCAG GAGCAGCTTCAGCAGAGCTTGCCAGTGAAGCAGGGGTCCAGCAGCAGCCACT GGAGCTGAGGCCTGGAGAGTACAGGGTGCTGTTGTGTGTGGACATTGGCGAG ACCCGGGGGGGCGGGCACAGGCCGGAGCTGCTCCGAGAGCTACAGCGGCTG CACGTGACCCACACGGTGCGCAAGCTGCACGTTGGAGATTTTGTGTGGGTGG CCCAGGAGACCAATCCTAGAGACCCAGCAAACCCTGGGGAGTTGGTACTGGA TCACATTGTGGAGCGCAAGCGACTGGATGACCTTTGCAGCAGCATCATCGAC GGCCGCTTCCGGGAGCAGAAGTTCCGGCTGAAGCGCTGTGGTCTGGAGCGCC GGGTATACCTGGTGGAAGAGCATGGTTCCGTCCACAACCTCAGCCTTCCTGA GAGCACACTGCTGCAGGCTGTCACCAACACTCAGGTCATTGATGGCTTTTTTG

TGAAGCGCACAGCAGACATTAAGGAGTCAGCCGCCTACCTGGCCCTCTTGAC GCGGGGCCTGCAGAGACTCTACCAGGGCCACACCCTACGCAGCCGCCCCTGG GGAACCCCTGGGAACCCTGAATCAGGGGCCATGACCTCTCCAAACCCTCTCT GCTCACTCCTCACCTTCAGTGACTTCAACGCAGGAGCCATCAAGAATAAGGC CCAGTCGGTGCGAGAAGTGTTTGCCCGGCAGCTGATGCAGGTGCGCGGAGTG AGTGGGGAGAAGGCAGCAGCCCTGGTGGATCGATACAGCACCCCTGCCAGC CTCCTGGCCGCCTATGATGCCTGTGCCACCCCCAAGGAACAAGAGACACTGC TGAGCACCATTAAGTGTGGGCGTCTACAGAGGAATCTGGGGCCTGCTCTGAG CAGGACCTTATCCCAGCTCTACTGCAGCTACGGCCCCTTGACCTGA Human MUS81 Protein Sequence, Variant 2 (SEQ ID NO: 59)

MAAPVRLGRKRPLPACPNPLFVRWLTEWRDEATRSRRRTRFVFQKALRSLRRYP

LPLRSGKEAKILQHFGDGLCRMLDERLQRHRTSGGDHAPDSPSGENSPAPQGRL

AEVQDSSMPVPAQPKAGGSGSYWPARHSGARVILLVLYREHLNPNGHHFLTKEE

LLQRCAQKSPRVAPGSARPWPALRSLLHRNLVLRTHQPARYSLTPEGLELAQKL

AESEGLSLLNVGIGPKEPPGEETAVPGAASAELASEAGVQQQPLELRPGEYRVLL

CVDIGETRGGGHRPELLRELQRLHVTHTVRKLHVGDFVWVAQETNPRDPANPG

ELVLDHIVERKRLDDLCSSIIDGRFREQKFRLKRCGLERRVYLVEEHGSVHNLSLP

ESTLLQAVTNTQVIDGFFVKRTADIKESAAYLALLTRGLQRLYQGHTLRSRPWGT

PGNPESGAMTSPNPLCSLLTFSDFNAGAIKNKAQSVREVFARQLMQVRGVSGEK

AAALVDRYSTPASLLAAYDACATPKEQETLLSTIKCGRLQRNLGPALSRTLSQLY

CSYGPLT

Human IFI16 cDNA Sequence, Variant 1 (SEQ ID NO: 60)

ATGGGAAAAAAATACAAGAACATTGTTCTACTAAAAGGATTAGAGGTCATCA

ATGATTATCATTTTAGAATGGTTAAGTCCTTACTGAGCAACGATTTAAAACTT

AATTTAAAAATGAGAGAAGAGTATGACAAAATTCAGATTGCTGACTTGATGG

AAGAAAAGTTCCGAGGTGATGCTGGTTTGGGCAAACTAATAAAAATTTTCGA

AGATATACCAACGCTTGAAGACCTGGCTGAAACTCTTAAAAAAGAAAAGTTA

AAAGTAAAAGGACCAGCCCTATCAAGAAAGAGGAAGAAGGAAGTGGATGCT

ACTTCACCTGCACCCTCCACAAGCAGCACTGTCAAAACTGAAGGAGCAGAGG

CAACTCCTGGAGCTCAGAAAAGAAAAAAATCAACCAAAGAAAAGGCTGGAC

CCAAAGGGAGTAAGGTGTCCGAGGAACAGACTCAGCCTCCCTCTCCTGCAGG

AGCCGGCATGTCCACAGCCATGGGCCGTTCCCCATCTCCCAAGACCTCATTGT

CAGCTCCACCCAACAGTTCTTCAACTGAGAACCCGAAAACAGTGGCCAAATG

TCAGGTAACTCCCAGAAGAAATGTTCTCCAAAAACGCCCAGTGATAGTGAAG

GTACTGAGTACAACAAAGCCATTTGAATATGAGACCCCAGAAATGGAGAAA

AAAATAATGTTTCATGCTACAGTGGCTACACAGACACAGTTCTTCCATGTGAA

GGTTTTAAACACCAGCTTGAAGGAGAAATTCAATGGAAAGAAAATCATCATC

ATATCAGATTATTTGGAATATGATAGTCTCCTAGAGGTCAATGAAGAATCTAC

TGTATCTGAAGCTGGTCCTAACCAAACGTTTGAGGTTCCAAATAAAATCATCA

ACAGAGCAAAGGAAACTCTGAAGATTGATATTCTTCACAAACAAGCTTCAGG

AAATATTGTATATGGGGTATTTATGCTACATAAGAAAACAGTAAATCAGAAG

ACCACAATCTACGAAATTCAGGATGATAGAGGAAAAATGGATGTAGTGGGG

ACAGGACAATGTCACAATATCCCCTGTGAAGAAGGAGATAAGCTCCAACTTT

TCTGCTTTCGACTTAGAAAAAAGAACCAGATGTCAAAACTGATTTCAGAAAT

GCATAGTTTTATCCAGATAAAGAAAAAAACAAACCCGAGAAACAATGACCCC

AAGAGCATGAAGCTACCCCAGGAACAGCGTCAGCTTCCATATCCTTCAGAGG

CCAGCACAACCTTCCCTGAGAGCCATCTTCGGACTCCTCAGATGCCACCAAC

AACTCCATCCAGCAGTTTCTTCACCAAGAAAAGTGAAGACACAATCTCCAAA

ATGAATGACTTCATGAGGATGCAGATACTGAAGGAAGGGAGTCATTTTCCAG

GACCGTTCATGACCAGCATAGGCCCAGCTGAGAGCCATCCCCACACTCCTCA

GATGCCTCCATCAACACCAAGCAGCAGTTTCTTAACCACGAAAAGTGAAGAC ACAATCTCCAAAATGAATGACTTCATGAGGATGCAGATACTGAAGGAAGGGA GTCATTTTCCAGGACCGTTCATGACCAGCATAGGCCCAGCTGAGAGCCATCC CCACACTCCTCAGATGCCTCCATCAACACCAAGCAGCAGTTTCTTAACCACGT

TGAAACCAAGACTGAAGACTGAACCTGAAGAAGTTTCCATAGAAGACAGTGC

CCAGAGTGACCTCAAAGAAGTGATGGTGCTGAACGCAACAGAATCATTTGTA

TATGAGCCCAAAGAGCAGAAGAAAATGTTTCATGCCACAGTGGCAACTGAGA

ATGAAGTCTTCCGAGTGAAGGTTTTTAATATTGACCTAAAGGAGAAGTTCAC

CCCAAAGAAGATCATTGCCATAGCAAATTATGTTTGCCGCAATGGGTTCCTG

GAGGTATATCCTTTCACACTTGTGGCTGATGTGAATGCTGACCGAAACATGG

AGATCCCAAAAGGATTGATTAGAAGTGCCAGCGTAACTCCTAAAATCAATCA

GCTTTGCTCACAAACTAAAGGAAGTTTTGTGAATGGGGTGTTTGAGGTACAT

AAGAAAAATGTAAGGGGTGAATTCACTTATTATGAAATACAAGATAATACAG

GGAAGATGGAAGTGGTGGTGCATGGACGACTGACCACAATCAACTGTGAGG

AAGGAGATAAACTGAAACTCACCTGCTTTGAATTGGCACCGAAAAGTGGGAA

TACCGGGGAGTTGAGATCTGTAATTCATAGTCACATCAAGGTCATCAAGACC AGGAAAAACAAGAAAGACATACTCAATCCTGATTCAAGTATGGAAACTTCAC CAGACTTTTTCTTCTAA

Human IFI16 Protein Sequence, Variant 1 (SEQ ID NO: 61)

MGKKYKNIVLLKGLEVINDYHFRMVKSLLSNDLKLNLKMREEYDKIQIADLMEE

KFRGDAGLGKLIKIFEDIPTLEDLAETLKKEKLKVKGPALSRKRKKEVDATSPAPS

TSSTVKTEGAEATPGAQKRKKSTKEKAGPKGSKVSEEQTQPPSPAGAGMSTAMG

RSPSPKTSLSAPPNSSSTENPKTVAKCQVTPRRNVLQKRPVIVKVLSTTKPFEYET

PEMEKKIMFHATVATQTQFFHVKVLNTSLKEKFNGKKIIIISDYLEYDSLLEVNEE

STVSEAGPNQTFEVPNKIINRAKETLKIDILHKQASGNIVYGVFMLHKKTVNQKT

TIYEIQDDRGKMDVVGTGQCHNIPCEEGDKLQLFCFRLRKKNQMSKLISEMHSFI

QIKKKTNPRNNDPKSMKLPQEQRQLPYPSEASTTFPESHLRTPQMPPTTPSSSFFT

KKSEDTISKMNDFMRMQILKEGSHFPGPFMTSIGPAESHPHTPQMPPSTPSSSFLT

TKSEDTISKMNDFMRMQILKEGSHFPGPFMTSIGPAESHPHTPQMPPSTPSSSFLTT

LKPRLKTEPEEVSIEDSAQSDLKEVMVLNATESFVYEPKEQKKMFHATVATENE

VFRVKVFNIDLKEKFTPKKIIAIANYVCRNGFLEVYPFTLVADVNADRNMEIPKG

LIRSASVTPKINQLCSQTKGSFVNGVFEVHKKNVRGEFTYYEIQDNTGKMEVVV

HGRLTTINCEEGDKLKLTCFELAPKSGNTGELRSVIHSHIKVIKTRKNKKDILNPD SSMETSPDFFF

Human IFI16 cDNA Sequence, Variant 2 (SEQ ID NO: 62)

ATGGGAAAAAAATACAAGAACATTGTTCTACTAAAAGGATTAGAGGTCATCA

ATGATTATCATTTTAGAATGGTTAAGTCCTTACTGAGCAACGATTTAAAACTT

AATTTAAAAATGAGAGAAGAGTATGACAAAATTCAGATTGCTGACTTGATGG

AAGAAAAGTTCCGAGGTGATGCTGGTTTGGGCAAACTAATAAAAATTTTCGA

AGATATACCAACGCTTGAAGACCTGGCTGAAACTCTTAAAAAAGAAAAGTTA

AAAGTAAAAGGACCAGCCCTATCAAGAAAGAGGAAGAAGGAAGTGGATGCT ACTTCACCTGCACCCTCCACAAGCAGCACTGTCAAAACTGAAGGAGCAGAGG CAACTCCTGGAGCTCAGAAAAGAAAAAAATCAACCAAAGAAAAGGCTGGAC CCAAAGGGAGTAAGGTGTCCGAGGAACAGACTCAGCCTCCCTCTCCTGCAGG AGCCGGCATGTCCACAGCCATGGGCCGTTCCCCATCTCCCAAGACCTCATTGT CAGCTCCACCCAACAGTTCTTCAACTGAGAACCCGAAAACAGTGGCCAAATG TCAGGTAACTCCCAGAAGAAATGTTCTCCAAAAACGCCCAGTGATAGTGAAG GTACTGAGTACAACAAAGCCATTTGAATATGAGACCCCAGAAATGGAGAAA AAAATAATGTTTCATGCTACAGTGGCTACACAGACACAGTTCTTCCATGTGAA GGTTTTAAACACCAGCTTGAAGGAGAAATTCAATGGAAAGAAAATCATCATC ATATCAGATTATTTGGAATATGATAGTCTCCTAGAGGTCAATGAAGAATCTAC TGTATCTGAAGCTGGTCCTAACCAAACGTTTGAGGTTCCAAATAAAATCATCA ACAGAGCAAAGGAAACTCTGAAGATTGATATTCTTCACAAACAAGCTTCAGG AAATATTGTATATGGGGTATTTATGCTACATAAGAAAACAGTAAATCAGAAG ACCACAATCTACGAAATTCAGGATGATAGAGGAAAAATGGATGTAGTGGGG ACAGGACAATGTCACAATATCCCCTGTGAAGAAGGAGATAAGCTCCAACTTT TCTGCTTTCGACTTAGAAAAAAGAACCAGATGTCAAAACTGATTTCAGAAAT GCATAGTTTTATCCAGATAAAGAAAAAAACAAACCCGAGAAACAATGACCCC AAGAGCATGAAGCTACCCCAGGAACAGCGTCAGCTTCCATATCCTTCAGAGG CCAGCACAACCTTCCCTGAGAGCCATCTTCGGACTCCTCAGATGCCACCAAC AACTCCATCCAGCAGTTTCTTCACCAAGAAAAGTGAAGACACAATCTCCAAA ATGAATGACTTCATGAGGATGCAGATACTGAAGGAAGGGAGTCATTTTCCAG GACCGTTCATGACCAGCATAGGCCCAGCTGAGAGCCATCCCCACACTCCTCA GATGCCTCCATCAACACCAAGCAGCAGTTTCTTAACCACGTTGAAACCAAGA CTGAAGACTGAACCTGAAGAAGTTTCCATAGAAGACAGTGCCCAGAGTGACC TCAAAGAAGTGATGGTGCTGAACGCAACAGAATCATTTGTATATGAGCCCAA AGAGCAGAAGAAAATGTTTCATGCCACAGTGGCAACTGAGAATGAAGTCTTC CGAGTGAAGGTTTTTAATATTGACCTAAAGGAGAAGTTCACCCCAAAGAAGA TCATTGCCATAGCAAATTATGTTTGCCGCAATGGGTTCCTGGAGGTATATCCT TTCACACTTGTGGCTGATGTGAATGCTGACCGAAACATGGAGATCCCAAAAG GATTGATTAGAAGTGCCAGCGTAACTCCTAAAATCAATCAGCTTTGCTCACA AACTAAAGGAAGTTTTGTGAATGGGGTGTTTGAGGTACATAAGAAAAATGTA AGGGGTGAATTCACTTATTATGAAATACAAGATAATACAGGGAAGATGGAAG TGGTGGTGCATGGACGACTGACCACAATCAACTGTGAGGAAGGAGATAAACT GAAACTCACCTGCTTTGAATTGGCACCGAAAAGTGGGAATACCGGGGAGTTG AGATCTGTAATTCATAGTCACATCAAGGTCATCAAGACCAGGAAAAACAAGA AAGACATACTCAATCCTGATTCAAGTATGGAAACTTCACCAGACTTTTTCTTC

TAA

Human IFI16 Protein Sequence, Variant 2 (SEQ ID NO: 63)

MGKKYKNIVLLKGLEVINDYHFRMVKSLLSNDLKLNLKMREEYDKIQIADLMEE KFRGDAGLGKLIKIFEDIPTLEDLAETLKKEKLKVKGPALSRKRKKEVDATSPAPS TSSTVKTEGAEATPGAQKRKKSTKEKAGPKGSKVSEEQTQPPSPAGAGMSTAMG RSPSPKTSLSAPPNSSSTENPKTVAKCQVTPRRNVLQKRPVIVKVLSTTKPFEYET PEMEKKIMFHATVATQTQFFHVKVLNTSLKEKFNGKKIIIISDYLEYDSLLEVNEE STVSEAGPNQTFEVPNKIINRAKETLKIDILHKQASGNIVYGVFMLHKKTVNQKT TIYEIQDDRGKMDVVGTGQCHNIPCEEGDKLQLFCFRLRKKNQMSKLISEMHSFI

QIKKKTNPRNNDPKSMKLPQEQRQLPYPSEASTTFPESHLRTPQMPPTTPSSSFFT

KKSEDTISKMNDFMRMQILKEGSHFPGPFMTSIGPAESHPHTPQMPPSTPSSSFLT

TLKPRLKTEPEEVSIEDSAQSDLKEVMVLNATESFVYEPKEQKKMFHATVATENE

VFRVKVFNIDLKEKFTPKKIIAIANYVCRNGFLEVYPFTLVADVNADRNMEIPKG

LIRSASVTPKINQLCSQTKGSFVNGVFEVHKKNVRGEFTYYEIQDNTGKMEVVV

HGRLTTINCEEGDKLKLTCFELAPKSGNTGELRSVIHSHIKVIKTRKNKKDILNPD SSMETSPDFFF

Human IFI16 cDNA Sequence, Variant 3 (SEQ ID NO: 64)

ATGGGAAAAAAATACAAGAACATTGTTCTACTAAAAGGATTAGAGGTCATCA

ATGATTATCATTTTAGAATGGTTAAGTCCTTACTGAGCAACGATTTAAAACTT

AATTTAAAAATGAGAGAAGAGTATGACAAAATTCAGATTGCTGACTTGATGG

AAGAAAAGTTCCGAGGTGATGCTGGTTTGGGCAAACTAATAAAAATTTTCGA

AGATATACCAACGCTTGAAGACCTGGCTGAAACTCTTAAAAAAGAAAAGTTA

AAAGTAAAAGGACCAGCCCTATCAAGAAAGAGGAAGAAGGAAGTGGATGCT

ACTTCACCTGCACCCTCCACAAGCAGCACTGTCAAAACTGAAGGAGCAGAGG

CAACTCCTGGAGCTCAGAACCCGAAAACAGTGGCCAAATGTCAGGTAACTCC

CAGAAGAAATGTTCTCCAAAAACGCCCAGTGATAGTGAAGGTACTGAGTACA

ACAAAGCCATTTGAATATGAGACCCCAGAAATGGAGAAAAAAATAATGTTTC

ATGCTACAGTGGCTACACAGACACAGTTCTTCCATGTGAAGGTTTTAAACACC

AGCTTGAAGGAGAAATTCAATGGAAAGAAAATCATCATCATATCAGATTATT

TGGAATATGATAGTCTCCTAGAGGTCAATGAAGAATCTACTGTATCTGAAGC

TGGTCCTAACCAAACGTTTGAGGTTCCAAATAAAATCATCAACAGAGCAAAG

GAAACTCTGAAGATTGATATTCTTCACAAACAAGCTTCAGGAAATATTGTAT

ATGGGGTATTTATGCTACATAAGAAAACAGTAAATCAGAAGACCACAATCTA

CGAAATTCAGGATGATAGAGGAAAAATGGATGTAGTGGGGACAGGACAATG

TCACAATATCCCCTGTGAAGAAGGAGATAAGCTCCAACTTTTCTGCTTTCGAC

TTAGAAAAAAGAACCAGATGTCAAAACTGATTTCAGAAATGCATAGTTTTAT

CCAGATAAAGAAAAAAACAAACCCGAGAAACAATGACCCCAAGAGCATGAA

GCTACCCCAGGAACAGCGTCAGCTTCCATATCCTTCAGAGGCCAGCACAACC

TTCCCTGAGAGCCATCTTCGGACTCCTCAGATGCCACCAACAACTCCATCCAG

CAGTTTCTTCACCAAGAAAAGTGAAGACACAATCTCCAAAATGAATGACTTC

ATGAGGATGCAGATACTGAAGGAAGGGAGTCATTTTCCAGGACCGTTCATGA

CCAGCATAGGCCCAGCTGAGAGCCATCCCCACACTCCTCAGATGCCTCCATC

AACACCAAGCAGCAGTTTCTTAACCACGAAAAGTGAAGACACAATCTCCAAA

ATGAATGACTTCATGAGGATGCAGATACTGAAGGAAGGGAGTCATTTTCCAG

GACCGTTCATGACCAGCATAGGCCCAGCTGAGAGCCATCCCCACACTCCTCA

GATGCCTCCATCAACACCAAGCAGCAGTTTCTTAACCACGTTGAAACCAAGA

CTGAAGACTGAACCTGAAGAAGTTTCCATAGAAGACAGTGCCCAGAGTGACC

TCAAAGAAGTGATGGTGCTGAACGCAACAGAATCATTTGTATATGAGCCCAA

AGAGCAGAAGAAAATGTTTCATGCCACAGTGGCAACTGAGAATGAAGTCTTC CGAGTGAAGGTTTTTAATATTGACCTAAAGGAGAAGTTCACCCCAAAGAAGA TCATTGCCATAGCAAATTATGTTTGCCGCAATGGGTTCCTGGAGGTATATCCT TTCACACTTGTGGCTGATGTGAATGCTGACCGAAACATGGAGATCCCAAAAG

GATTGATTAGAAGTGCCAGCGTAACTCCTAAAATCAATCAGCTTTGCTCACA AACTAAAGGAAGTTTTGTGAATGGGGTGTTTGAGGTACATAAGAAAAATGTA

AGGGGTGAATTCACTTATTATGAAATACAAGATAATACAGGGAAGATGGAAG TGGTGGTGCATGGACGACTGACCACAATCAACTGTGAGGAAGGAGATAAACT GAAACTCACCTGCTTTGAATTGGCACCGAAAAGTGGGAATACCGGGGAGTTG AGATCTGTAATTCATAGTCACATCAAGGTCATCAAGACCAGGAAAAACAAGA AAGACATACTCAATCCTGATTCAAGTATGGAAACTTCACCAGACTTTTTCTTC

TAA

Human IFI16 Protein Sequence, Variant 3 (SEQ ID NO: 65)

MGKKYKNIVLLKGLEVINDYHFRMVKSLLSNDLKLNLKMREEYDKIQIADLMEE KFRGDAGLGKLIKIFEDIPTLEDLAETLKKEKLKVKGPALSRKRKKEVDATSPAPS TSSTVKTEGAEATPGAQNPKTVAKCQVTPRRNVLQKRPVIVKVLSTTKPFEYETP EMEKKIMFHATVATQTQFFHVKVLNTSLKEKFNGKKIIIISDYLEYDSLLEVNEES

TVSEAGPNQTFEVPNKIINRAKETLKIDILHKQASGNIVYGVFMLHKKTVNQKTTI YEIQDDRGKMDVVGTGQCHNIPCEEGDKLQLFCFRLRKKNQMSKLISEMHSFIQI KKKTNPRNNDPKSMKLPQEQRQLPYPSEASTTFPESHLRTPQMPPTTPSSSFFTKK SEDTISKMNDFMRMQILKEGSHFPGPFMTSIGPAESHPHTPQMPPSTPSSSFLTTKS EDTISKMNDFMRMQILKEGSHFPGPFMTSIGPAESHPHTPQMPPSTPSSSFLTTLKP

RLKTEPEEVSIEDSAQSDLKEVMVLNATESFVYEPKEQKKMFHATVATENEVFR VKVFNIDLKEKFTPKKIIAIANYVCRNGFLEVYPFTLVADVNADRNMEIPKGLIRS

ASVTPKINQLCSQTKGSFVNGVFEVHKKNVRGEFTYYEIQDNTGKMEVVVHGRL TTINCEEGDKLKLTCFELAPKSGNTGELRSVIHSHIKVIKTRKNKKDILNPDSSME

TSPDFFF

Human cGAS cDNA Sequence (SEQ ID NO: 66)

ATGCAGCCTTGGCACGGAAAGGCCATGCAGAGAGCTTCCGAGGCCGGAGCC

ACTGCCCCCAAGGCTTCCGCACGGAATGCCAGGGGCGCCCCGATGGATCCCA CCGAGTCTCCGGCTGCCCCCGAGGCCGCCCTGCCTAAGGCGGGAAAGTTCGG CCCCGCCAGGAAGTCGGGATCCCGGCAGAAAAAGAGCGCCCCGGACACCCA

GGAGAGGCCGCCCGTCCGCGCAACTGGGGCCCGCGCCAAAAAGGCCCCTCA GCGCGCCCAGGACACGCAGCCGTCTGACGCCACCAGCGCCCCTGGGGCAGA

GGGGCTGGAGCCTCCTGCGGCTCGGGAGCCGGCTCTTTCCAGGGCTGGTTCTT GCCGCCAGAGGGGCGCGCGCTGCTCCACGAAGCCAAGACCTCCGCCCGGGCC CTGGGACGTGCCCAGCCCCGGCCTGCCGGTCTCGGCCCCCATTCTCGTACGG

AGGGATGCGGCGCCTGGGGCCTCGAAGCTCCGGGCGGTTTTGGAGAAGTTGA

AGCTCAGCCGCGATGATATCTCCACGGCGGCGGGGATGGTGAAAGGGGTTGT GGACCACCTGCTGCTCAGACTGAAGTGCGACTCCGCGTTCAGAGGCGTCGGG CTGCTGAACACCGGGAGCTACTATGAGCACGTGAAGATTTCTGCACCTAATG

AATTTGATGTCATGTTTAAACTGGAAGTCCCCAGAATTCAACTAGAAGAATA TTCCAACACTCGTGCATATTACTTTGTGAAATTTAAAAGAAATCCGAAAGAA

AATCCTCTGAGTCAGTTTTTAGAAGGTGAAATATTATCAGCTTCTAAGATGCT GTCAAAGTTTAGGAAAATCATTAAGGAAGAAATTAACGACATTAAAGATACA GATGTCATCATGAAGAGGAAAAGAGGAGGGAGCCCTGCTGTAACACTTCTTA TTAGTGAAAAAATATCTGTGGATATAACCCTGGCTTTGGAATCAAAAAGTAG CTGGCCTGCTAGCACCCAAGAAGGCCTGCGCATTCAAAACTGGCTTTCAGCA AAAGTTAGGAAGCAACTACGACTAAAGCCATTTTACCTTGTACCCAAGCATG CAAAGGAAGGAAATGGTTTCCAAGAAGAAACATGGCGGCTATCCTTCTCTCA

CATCGAAAAGGAAATTTTGAACAATCATGGAAAATCTAAAACGTGCTGTGAA AACAAAGAAGAGAAATGTTGCAGGAAAGATTGTTTAAAACTAATGAAATAC

CTTTTAGAACAGCTGAAAGAAAGGTTTAAAGACAAAAAACATCTGGATAAAT TCTCTTCTTATCATGTGAAAACTGCCTTCTTTCACGTATGTACCCAGAACCCTC AAGACAGTCAGTGGGACCGCAAAGACCTGGGCCTCTGCTTTGATAACTGCGT GACATACTTTCTTCAGTGCCTCAGGACAGAAAAACTTGAGAATTATTTTATTC

CTGAATTCAATCTATTCTCTAGCAACTTAATTGACAAAAGAAGTAAGGAATTT CTGACAAAGCAAATTGAATATGAAAGAAACAATGAGTTTCCAGTTTTTGATG AATTTTGA

Human cGAS Protein Sequence (SEQ ID NO: 67)

MQPWHGKAMQRASEAGATAPKASARNARGAPMDPTESPAAPEAALPKAGKFG PARKSGSRQKKSAPDTQERPPVRATGARAKKAPQRAQDTQPSDATSAPGAEGLE PPAAREPALSRAGSCRQRGARCSTKPRPPPGPWDVPSPGLPVSAPILVRRDAAPG ASKLRAVLEKLKLSRDDISTAAGMVKGVVDHLLLRLKCDSAFRGVGLLNTGSY

YEHVKISAPNEFDVMFKLEVPRIQLEEYSNTRAYYFVKFKRNPKENPLSQFLEGEI LSASKMLSKFRKIIKEEINDIKDTDVIMKRKRGGSPAVTLLISEKISVDITLALESKS SWPASTQEGLRIQNWLSAKVRKQLRLKPFYLVPKHAKEGNGFQEETWRLSFSHI EKEILNNHGKSKTCCENKEEKCCRKDCLKLMKYLLEQLKERFKDKKHLDKF S SY HVKTAFFHVCTQNPQDSQWDRKDLGLCFDNCVTYFLQCLRTEKLENYFIPEFNL F S SNLIDKRSKEFLTKQIEYERNNEFP VFDEF

Human DDX41 cDNA Sequence, Variant 1 (SEQ ID NO: 68)

ATGGAGGAGTCGGAACCCGAACGGAAGCGGGCTCGCACCGACGAGGTGCCT GCCGGAGGAAGCCGCTCCGAGGCGGAAGATGAGGACGACGAGGACTACGTG CCCTATGTGCCGTTACGGCAGCGCCGGCAGCTACTGCTCCAGAAGCTGCTGC

AGCGAAGACGCAAGGGAGCTGCGGAGGAAGAGCAGCAGGACAGCGGTAGTG AACCCCGGGGAGATGAGGACGACATCCCGCTAGGCCCTCAGTCCAACGTCAG CCTCCTGGATCAGCACCAGCACCTTAAAGAGAAGGCTGAAGCGCGCAAAGA GTCTGCCAAGGAGAAGCAGCTGAAGGAAGAAGAGAAGATCCTGGAGAGTGT TGCCGAGGGCCGAGCATTGATGTCAGTGAAGGAGATGGCTAAGGGCATTACG

TATGATGACCCCATCAAAACCAGCTGGACTCCACCCCGTTATGTTCTGAGCAT GTCTGAAGAGCGACATGAGCGCGTGCGGAAGAAATACCACATCCTGGTGGA GGGAGACGGTATCCCACCACCCATCAAGAGCTTCAAGGAAATGAAGTTTCCT GCAGCCATCCTGAGAGGCCTGAAGAAGAAAGGCATTCACCACCCAACACCC ATTCAGATCCAGGGCATCCCCACCATTCTATCTGGCCGTGACATGATAGGCAT CGCTTTCACGGGTTCAGGCAAGACACTGGTGTTCACGTTGCCCGTCATCATGT TCTGCCTGGAACAAGAGAAGAGGTTACCCTTCTCAAAGCGCGAGGGGCCCTA TGGACTCATCATCTGCCCCTCGCGGGAGCTGGCCCGGCAGACCCATGGCATC CTGGAGTACTACTGCCGCCTGCTGCAGGAGGACAGCTCACCACTCCTGCGCT GCGCCCTCTGCATTGGGGGCATGTCCGTGAAAGAGCAGATGGAGACCATCCG ACACGGTGTACACATGATGGTGGCCACCCCGGGGCGCCTCATGGATTTGCTG CAGAAGAAGATGGTCAGCCTAGACATCTGTCGCTACCTGGCCCTGGACGAGG CTGACCGCATGATCGACATGGGCTTCGAGGGTGACATCCGTACCATCTTCTCC TACTTCAAGGGCCAGCGACAGACCCTGCTCTTCAGTGCCACCATGCCGAAGA AGATTCAGAACTTTGCTAAGAGTGCCCTTGTAAAGCCTGTGACCATCAATGTG GGGCGCGCTGGGGCTGCCAGCCTGGATGTCATCCAGGAGGTAGAATATGTGA

AGGAGGAGGCCAAGATGGTGTACCTGCTCGAGTGCCTGCAGAAGACACCCCC GCCTGTACTCATCTTTGCAGAGAAGAAGGCAGACGTGGACGCCATCCACGAG TACCTGCTGCTCAAGGGGGTTGAGGCCGTAGCCATCCATGGGGGCAAAGACC AGGAGGAACGGACTAAGGCCATCGAGGCATTCCGGGAGGGCAAGAAGGATG TCCTAGTAGCCACAGACGTTGCCTCCAAGGGCCTGGACTTCCCTGCCATCCAG CACGTCATCAATTATGACATGCCAGAGGAGATTGAGAACTATGTACACCGGA TTGGCCGCACCGGGCGCTCGGGAAACACAGGCATCGCCACTACCTTCATCAA CAAAGCGTGTGATGAGTCAGTGCTGATGGACCTCAAAGCGCTGCTGCTAGAA GCCAAGCAGAAGGTGCCGCCCGTGCTGCAGGTGCTGCATTGCGGGGATGAGT CCATGCTGGACATTGGAGGAGAGCGCGGCTGTGCCTTCTGCGGGGGCCTGGG

TCATCGGATCACTGACTGCCCCAAACTCGAGGCTATGCAGACCAAGCAGGTC AGCAACATCGGTCGCAAGGACTACCTGGCCCACAGCTCCATGGACTTCTGA

Human DDX41 Protein Sequence, Variant 1 (SEQ ID NO: 69)

MEESEPERKRARTDEVPAGGSRSEAEDEDDEDYVPYVPLRQRRQLLLQKLLQRR RKGAAEEEQQDSGSEPRGDEDDIPLGPQSNVSLLDQHQHLKEKAEARKESAKEK QLKEEEKILESVAEGRALMSVKEMAKGITYDDPIKTSWTPPRYVLSMSEERHERV RKKYHILVEGDGIPPPIKSFKEMKFPAAILRGLKKKGIHHPTPIQIQGIPTILSGRDM IGIAFTGSGKTLVFTLPVIMFCLEQEKRLPFSKREGPYGLIICPSRELARQTHGILEY YCRLLQEDSSPLLRCALCIGGMSVKEQMETIRHGVHMMVATPGRLMDLLQKKM VSLDICRYLALDEADRMIDMGFEGDIRTIF S YFKGQRQTLLF S ATMPKKIQNF AKS ALVKPVTINVGRAGAASLDVIQEVEYVKEEAKMVYLLECLQKTPPPVLIFAEKK ADVDAIHEYLLLKGVEAVAIHGGKDQEERTKAIEAFREGKKDVLVATDVASKGL DFPAIQHVINYDMPEEIENYVHRIGRTGRSGNTGIATTFINKACDESVLMDLKALL

LEAKQKVPPVLQVLHCGDESMLDIGGERGCAFCGGLGHRITDCPKLEAMQTKQ VSNIGRKD YL AHS SMDF

Human DDX41 cDNA Sequence, Variant 2 (SEQ ID NO: 70)

ATGTCAGTGAAGGAGATGGCTAAGGGCATTACGTATGATGACCCCATCAAAA CCAGCTGGACTCCACCCCGTTATGTTCTGAGCATGTCTGAAGAGCGACATGA GCGCGTGCGGAAGAAATACCACATCCTGGTGGAGGGAGACGGTATCCCACC ACCCATCAAGAGCTTCAAGGAAATGAAGTTTCCTGCAGCCATCCTGAGAGGC CTGAAGAAGAAAGGCATTCACCACCCAACACCCATTCAGATCCAGGGCATCC CCACCATTCTATCTGGCCGTGACATGATAGGCATCGCTTTCACGGGTTCAGGC AAGACACTGGTGTTCACGTTGCCCGTCATCATGTTCTGCCTGGAACAAGAGA AGAGGTTACCCTTCTCAAAGCGCGAGGGGCCCTATGGACTCATCATCTGCCC CTCGCGGGAGCTGGCCCGGCAGACCCATGGCATCCTGGAGTACTACTGCCGC CTGCTGCAGGAGGACAGCTCACCACTCCTGCGCTGCGCCCTCTGCATTGGGG GCATGTCCGTGAAAGAGCAGATGGAGACCATCCGACACGGTGTACACATGAT GGTGGCCACCCCGGGGCGCCTCATGGATTTGCTGCAGAAGAAGATGGTCAGC CTAGACATCTGTCGCTACCTGGCCCTGGACGAGGCTGACCGCATGATCGACA TGGGCTTCGAGGGTGACATCCGTACCATCTTCTCCTACTTCAAGGGCCAGCGA

CAGACCCTGCTCTTCAGTGCCACCATGCCGAAGAAGATTCAGAACTTTGCTA AGAGTGCCCTTGTAAAGCCTGTGACCATCAATGTGGGGCGCGCTGGGGCTGC CAGCCTGGATGTCATCCAGGAGGTAGAATATGTGAAGGAGGAGGCCAAGAT GGTGTACCTGCTCGAGTGCCTGCAGAAGACACCCCCGCCTGTACTCATCTTTG CAGAGAAGAAGGCAGACGTGGACGCCATCCACGAGTACCTGCTGCTCAAGG GGGTTGAGGCCGTAGCCATCCATGGGGGCAAAGACCAGGAGGAACGGACTA AGGCCATCGAGGCATTCCGGGAGGGCAAGAAGGATGTCCTAGTAGCCACAG ACGTTGCCTCCAAGGGCCTGGACTTCCCTGCCATCCAGCACGTCATCAATTAT

GACATGCCAGAGGAGATTGAGAACTATGTACACCGGATTGGCCGCACCGGGC GCTCGGGAAACACAGGCATCGCCACTACCTTCATCAACAAAGCGTGTGATGA GTCAGTGCTGATGGACCTCAAAGCGCTGCTGCTAGAAGCCAAGCAGAAGGTG CCGCCCGTGCTGCAGGTGCTGCATTGCGGGGATGAGTCCATGCTGGACATTG GAGGAGAGCGCGGCTGTGCCTTCTGCGGGGGCCTGGGTCATCGGATCACTGA CTGCCCCAAACTCGAGGCTATGCAGACCAAGCAGGTCAGCAACATCGGTCGC AAGGACTACCTGGCCCACAGCTCCATGGACTTCTGA

Human DDX41 Protein Sequence, Variant 2 (SEQ ID NO: 71)

MSVKEMAKGITYDDPIKTSWTPPRYVLSMSEERHERVRKKYHILVEGDGIPPPIK SFKEMKFPAAILRGLKKKGIHHPTPIQIQGIPTILSGRDMIGIAFTGSGKTLVFTLPV

IMFCLEQEKRLPFSKREGPYGLIICPSRELARQTHGILEYYCRLLQEDSSPLLRCAL CIGGMSVKEQMETIRHGVHMMVATPGRLMDLLQKKMVSLDICRYLALDEADR MIDMGFEGDIRTIF S YFKGQRQTLLF S ATMPKKIQNF AKS ALVKP VTINVGRAGA ASLDVIQEVEYVKEEAKMVYLLECLQKTPPPVLIFAEKKADVDAIHEYLLLKGVE AVAIHGGKDQEERTKAIEAFREGKKDVLVATDVASKGLDFPAIQHVINYDMPEEI ENYVHRIGRTGRSGNTGIATTFINKACDESVLMDLKALLLEAKQKVPPVLQVLH CGDESMLDIGGERGCAFCGGLGHRITDCPKLEAMQTKQVSNIGRKDYLAHSSMD F

Human EXO1 cDNA Sequence, Variant 1 (SEQ ID NO: 72)

ATGGGGATACAGGGATTGCTACAATTTATCAAAGAAGCTTCAGAACCCATCC ATGTGAGGAAGTATAAAGGGCAGGTAGTAGCTGTGGATACATATTGCTGGCT TCACAAAGGAGCTATTGCTTGTGCTGAAAAACTAGCCAAAGGTGAACCTACT GATAGGTATGTAGGATTTTGTATGAAATTTGTAAATATGTTACTATCTCATGG GATCAAGCCTATTCTCGTATTTGATGGATGTACTTTACCTTCTAAAAAGGAAG TAGAGAGATCTAGAAGAGAAAGACGACAAGCCAATCTTCTTAAGGGAAAGC

AACTTCTTCGTGAGGGGAAAGTCTCGGAAGCTCGAGAGTGTTTCACCCGGTC

TATCAATATCACACATGCCATGGCCCACAAAGTAATTAAAGCTGCCCGGTCT

CAGGGGGTAGATTGCCTCGTGGCTCCCTATGAAGCTGATGCGCAGTTGGCCT

ATCTTAACAAAGCGGGAATTGTGCAAGCCATAATTACAGAGGACTCGGATCT

CCTAGCTTTTGGCTGTAAAAAGGTAATTTTAAAGATGGACCAGTTTGGAAAT

GGACTTGAAATTGATCAAGCTCGGCTAGGAATGTGCAGACAGCTTGGGGATG

TATTCACGGAAGAGAAGTTTCGTTACATGTGTATTCTTTCAGGTTGTGACTAC

CTGTCATCACTGCGTGGGATTGGATTAGCAAAGGCATGCAAAGTCCTAAGAC

TAGCCAATAATCCAGATATAGTAAAGGTTATCAAGAAAATTGGACATTATCT

CAAGATGAATATCACGGTACCAGAGGATTACATCAACGGGTTTATTCGGGCC

AACAATACCTTCCTCTATCAGCTAGTTTTTGATCCCATCAAAAGGAAACTTAT

TCCTCTGAACGCCTATGAAGATGATGTTGATCCTGAAACACTAAGCTACGCTG

GGCAATATGTTGATGATTCCATAGCTCTTCAAATAGCACTTGGAAATAAAGA

TATAAATACTTTTGAACAGATCGATGACTACAATCCAGACACTGCTATGCCTG

CCCATTCAAGAAGTCATAGTTGGGATGACAAAACATGTCAAAAGTCAGCTAA

TGTTAGCAGCATTTGGCATAGGAATTACTCTCCCAGACCAGAGTCGGGTACT

GTTTCAGATGCCCCACAATTGAAGGAAAATCCAAGTACTGTGGGAGTGGAAC

GAGTGATTAGTACTAAAGGGTTAAATCTCCCAAGGAAATCATCCATTGTGAA

AAGACCAAGAAGTGCAGAGCTGTCAGAAGATGACCTGTTGAGTCAGTATTCT

CTTTCATTTACGAAGAAGACCAAGAAAAATAGCTCTGAAGGCAATAAATCAT

TGAGCTTTTCTGAAGTGTTTGTGCCTGACCTGGTAAATGGACCTACTAACAAA

AAGAGTGTAAGCACTCCACCTAGGACGAGAAATAAATTTGCAACATTTTTAC

AAAGGAAAAATGAAGAAAGTGGTGCAGTTGTGGTTCCAGGGACCAGAAGCA

GGTTTTTTTGCAGTTCAGATTCTACTGACTGTGTATCAAACAAAGTGAGCATC

CAGCCTCTGGATGAAACTGCTGTCACAGATAAAGAGAACAATCTGCATGAAT

CAGAGTATGGAGACCAAGAAGGCAAGAGACTGGTTGACACAGATGTAGCAC

GTAATTCAAGTGATGACATTCCGAATAATCATATTCCAGGTGATCATATTCCA

GACAAGGCAACAGTGTTTACAGATGAAGAGTCCTACTCTTTTGAGAGCAGCA

AATTTACAAGGACCATTTCACCACCCACTTTGGGAACACTAAGAAGTTGTTTT

AGTTGGTCTGGAGGTCTTGGAGATTTTTCAAGAACGCCGAGCCCCTCTCCAAG

CACAGCATTGCAGCAGTTCCGAAGAAAGAGCGATTCCCCCACCTCTTTGCCT

GAGAATAATATGTCTGATGTGTCGCAGTTAAAGAGCGAGGAGTCCAGTGACG

ATGAGTCTCATCCCTTACGAGAAGAGGCATGTTCTTCACAGTCCCAGGAAAG

TGGAGAATTCTCACTGCAGAGTTCAAATGCATCAAAGCTTTCTCAGTGCTCTA

GTAAGGACTCTGATTCAGAGGAATCTGATTGCAATATTAAGTTACTTGACAGT

CAAAGTGACCAGACCTCCAAGCTACGTTTATCTCATTTCTCAAAAAAAGACA

CACCTCTAAGGAACAAGGTTCCTGGGCTATATAAGTCCAGTTCTGCAGACTCT

CTTTCTACAACCAAGATCAAACCTCTAGGACCTGCCAGAGCCAGTGGGCTGA

GCAAGAAGCCGGCAAGCATCCAGAAGAGAAAGCATCATAATGCCGAGAACA

AGCCGGGGTTACAGATCAAACTCAATGAGCTCTGGAAAAACTTTGGATTTAA

AAAAGATTCTGAAAAGCTTCCTCCTTGTAAGAAACCCCTGTCCCCAGTCAGA

GATAACATCCAACTAACTCCAGAAGCGGAAGAGGATATATTTAACAAACCTG

AATGTGGCCGTGTTCAAAGAGCAATATTCCAGTAA Human EXO1 Protein Sequence, Variant 1 (SEQ ID NO: 73)

MGIQGLLQFIKEASEPIHVRKYKGQVVAVDTYCWLHKGAIACAEKLAKGEPTDR

YVGFCMKFVNMLLSHGIKPILVFDGCTLPSKKEVERSRRERRQANLLKGKQLLR

EGKVSEARECFTRSINITHAMAHKVIKAARSQGVDCLVAPYEADAQLAYLNKAG

IVQAIITEDSDLLAFGCKKVILKMDQFGNGLEIDQARLGMCRQLGDVFTEEKFRY

MCILSGCDYLSSLRGIGLAKACKVLRLANNPDIVKVIKKIGHYLKMNITVPEDYIN

GFIRANNTFLYQLVFDPIKRKLIPLNAYEDDVDPETLSYAGQYVDDSIALQIALGN

KDINTFEQIDDYNPDTAMPAHSRSHSWDDKTCQKSANVSSIWHRNYSPRPESGT

VSDAPQLKENPSTVGVERVISTKGLNLPRKSSIVKRPRSAELSEDDLLSQYSLSFT

KKTKKNSSEGNKSLSFSEVFVPDLVNGPTNKKSVSTPPRTRNKFATFLQRKNEES

GAVVVPGTRSRFFCSSDSTDCVSNKVSIQPLDETAVTDKENNLHESEYGDQEGK

RLVDTD VARNS SDDIPNNHIPGDHIPDKATVFTDEES YSFES SKFTRTISPPTLGTL

RSCFSWSGGLGDFSRTPSPSPSTALQQFRRKSDSPTSLPENNMSDVSQLKSEESSD

DESHPLREEACSSQSQESGEFSLQSSNASKLSQCSSKDSDSEESDCNIKLLDSQSD

QTSKLRLSHFSKKDTPLRNKVPGLYKSSSADSLSTTKIKPLGPARASGLSKKPASI

QKRKHHNAENKPGLQIKLNELWKNFGFKKDSEKLPPCKKPLSPVRDNIQLTPEA EEDIFNKPECGRVQRAIFQ

Human EXO cDNA Sequence, Variant 2 (SEQ ID NO: 74)

ATGGGGATACAGGGATTGCTACAATTTATCAAAGAAGCTTCAGAACCCATCC

ATGTGAGGAAGTATAAAGGGCAGGTAGTAGCTGTGGATACATATTGCTGGCT

TCACAAAGGAGCTATTGCTTGTGCTGAAAAACTAGCCAAAGGTGAACCTACT

GATAGGTATGTAGGATTTTGTATGAAATTTGTAAATATGTTACTATCTCATGG

GATCAAGCCTATTCTCGTATTTGATGGATGTACTTTACCTTCTAAAAAGGAAG

TAGAGAGATCTAGAAGAGAAAGACGACAAGCCAATCTTCTTAAGGGAAAGC

AACTTCTTCGTGAGGGGAAAGTCTCGGAAGCTCGAGAGTGTTTCACCCGGTC

TATCAATATCACACATGCCATGGCCCACAAAGTAATTAAAGCTGCCCGGTCT

CAGGGGGTAGATTGCCTCGTGGCTCCCTATGAAGCTGATGCGCAGTTGGCCT

ATCTTAACAAAGCGGGAATTGTGCAAGCCATAATTACAGAGGACTCGGATCT

CCTAGCTTTTGGCTGTAAAAAGGTAATTTTAAAGATGGACCAGTTTGGAAAT

GGACTTGAAATTGATCAAGCTCGGCTAGGAATGTGCAGACAGCTTGGGGATG

TATTCACGGAAGAGAAGTTTCGTTACATGTGTATTCTTTCAGGTTGTGACTAC

CTGTCATCACTGCGTGGGATTGGATTAGCAAAGGCATGCAAAGTCCTAAGAC

TAGCCAATAATCCAGATATAGTAAAGGTTATCAAGAAAATTGGACATTATCT

CAAGATGAATATCACGGTACCAGAGGATTACATCAACGGGTTTATTCGGGCC

AACAATACCTTCCTCTATCAGCTAGTTTTTGATCCCATCAAAAGGAAACTTAT

TCCTCTGAACGCCTATGAAGATGATGTTGATCCTGAAACACTAAGCTACGCTG

GGCAATATGTTGATGATTCCATAGCTCTTCAAATAGCACTTGGAAATAAAGA

TATAAATACTTTTGAACAGATCGATGACTACAATCCAGACACTGCTATGCCTG

CCCATTCAAGAAGTCATAGTTGGGATGACAAAACATGTCAAAAGTCAGCTAA

TGTTAGCAGCATTTGGCATAGGAATTACTCTCCCAGACCAGAGTCGGGTACT

GTTTCAGATGCCCCACAATTGAAGGAAAATCCAAGTACTGTGGGAGTGGAAC

GAGTGATTAGTACTAAAGGGTTAAATCTCCCAAGGAAATCATCCATTGTGAA AAGACCAAGAAGTGAGCTGTCAGAAGATGACCTGTTGAGTCAGTATTCTCTT TCATTTACGAAGAAGACCAAGAAAAATAGCTCTGAAGGCAATAAATCATTGA GCTTTTCTGAAGTGTTTGTGCCTGACCTGGTAAATGGACCTACTAACAAAAAG AGTGTAAGCACTCCACCTAGGACGAGAAATAAATTTGCAACATTTTTACAAA GGAAAAATGAAGAAAGTGGTGCAGTTGTGGTTCCAGGGACCAGAAGCAGGT TTTTTTGCAGTTCAGATTCTACTGACTGTGTATCAAACAAAGTGAGCATCCAG CCTCTGGATGAAACTGCTGTCACAGATAAAGAGAACAATCTGCATGAATCAG AGTATGGAGACCAAGAAGGCAAGAGACTGGTTGACACAGATGTAGCACGTA ATTCAAGTGATGACATTCCGAATAATCATATTCCAGGTGATCATATTCCAGAC AAGGCAACAGTGTTTACAGATGAAGAGTCCTACTCTTTTGAGAGCAGCAAAT TTACAAGGACCATTTCACCACCCACTTTGGGAACACTAAGAAGTTGTTTTAGT TGGTCTGGAGGTCTTGGAGATTTTTCAAGAACGCCGAGCCCCTCTCCAAGCAC AGCATTGCAGCAGTTCCGAAGAAAGAGCGATTCCCCCACCTCTTTGCCTGAG

AATAATATGTCTGATGTGTCGCAGTTAAAGAGCGAGGAGTCCAGTGACGATG AGTCTCATCCCTTACGAGAAGAGGCATGTTCTTCACAGTCCCAGGAAAGTGG AGAATTCTCACTGCAGAGTTCAAATGCATCAAAGCTTTCTCAGTGCTCTAGTA AGGACTCTGATTCAGAGGAATCTGATTGCAATATTAAGTTACTTGACAGTCA AAGTGACCAGACCTCCAAGCTACGTTTATCTCATTTCTCAAAAAAAGACACA CCTCTAAGGAACAAGGTTCCTGGGCTATATAAGTCCAGTTCTGCAGACTCTCT TTCTACAACCAAGATCAAACCTCTAGGACCTGCCAGAGCCAGTGGGCTGAGC AAGAAGCCGGCAAGCATCCAGAAGAGAAAGCATCATAATGCCGAGAACAAG CCGGGGTTACAGATCAAACTCAATGAGCTCTGGAAAAACTTTGGATTTAAAA AAGATTCTGAAAAGCTTCCTCCTTGTAAGAAACCCCTGTCCCCAGTCAGAGAT AACATCCAACTAACTCCAGAAGCGGAAGAGGATATATTTAACAAACCTGAAT GTGGCCGTGTTCAAAGAGCAATATTCCAGTAA

Human EXO Protein Sequence, Variant 2 (SEQ ID NO: 75)

MGIQGLLQFIKEASEPIHVRKYKGQVVAVDTYCWLHKGAIACAEKLAKGEPTDR YVGFCMKFVNMLLSHGIKPILVFDGCTLPSKKEVERSRRERRQANLLKGKQLLR EGKVSEARECFTRSINITHAMAHKVIKAARSQGVDCLVAPYEADAQLAYLNKAG IVQAIITEDSDLLAFGCKKVILKMDQFGNGLEIDQARLGMCRQLGDVFTEEKFRY MCILSGCDYLSSLRGIGLAKACKVLRLANNPDIVKVIKKIGHYLKMNITVPEDYIN GFIRANNTFLYQLVFDPIKRKLIPLNAYEDDVDPETLSYAGQYVDDSIALQIALGN KDINTFEQIDDYNPDTAMPAHSRSHSWDDKTCQKSANVSSIWHRNYSPRPESGT VSDAPQLKENPSTVGVERVISTKGLNLPRKSSIVKRPRSELSEDDLLSQYSLSFTK

KTKKNSSEGNKSLSFSEVFVPDLVNGPTNKKSVSTPPRTRNKFATFLQRKNEESG AVVVPGTRSRFFCSSDSTDCVSNKVSIQPLDETAVTDKENNLHESEYGDQEGKRL VDTD VARNS SDDIPNNHIPGDHIPDKATVFTDEES YSFES SKFTRTISPPTLGTLRS CFSWSGGLGDFSRTPSPSPSTALQQFRRKSDSPTSLPENNMSDVSQLKSEESSDDE SHPLREEACSSQSQESGEFSLQSSNASKLSQCSSKDSDSEESDCNIKLLDSQSDQTS KLRLSHFSKKDTPLRNKVPGLYKSSSADSLSTTKIKPLGPARASGLSKKPASIQKR KHHNAENKPGLQIKLNELWKNFGFKKDSEKLPPCKKPLSPVRDNIQLTPEAEEDI FNKPECGRVQRAIFQ Human EXO cDNA Sequence, Variant 3 (SEQ ID NO: 76)

ATGGGGATACAGGGATTGCTACAATTTATCAAAGAAGCTTCAGAACCCATCC

ATGTGAGGAAGTATAAAGGGCAGGTAGTAGCTGTGGATACATATTGCTGGCT

TCACAAAGGAGCTATTGCTTGTGCTGAAAAACTAGCCAAAGGTGAACCTACT

GATAGGTATGTAGGATTTTGTATGAAATTTGTAAATATGTTACTATCTCATGG

GATCAAGCCTATTCTCGTATTTGATGGATGTACTTTACCTTCTAAAAAGGAAG

TAGAGAGATCTAGAAGAGAAAGACGACAAGCCAATCTTCTTAAGGGAAAGC

AACTTCTTCGTGAGGGGAAAGTCTCGGAAGCTCGAGAGTGTTTCACCCGGTC

TATCAATATCACACATGCCATGGCCCACAAAGTAATTAAAGCTGCCCGGTCT

CAGGGGGTAGATTGCCTCGTGGCTCCCTATGAAGCTGATGCGCAGTTGGCCT

ATCTTAACAAAGCGGGAATTGTGCAAGCCATAATTACAGAGGACTCGGATCT

CCTAGCTTTTGGCTGTAAAAAGGTAATTTTAAAGATGGACCAGTTTGGAAAT

GGACTTGAAATTGATCAAGCTCGGCTAGGAATGTGCAGACAGCTTGGGGATG

TATTCACGGAAGAGAAGTTTCGTTACATGTGTATTCTTTCAGGTTGTGACTAC

CTGTCATCACTGCGTGGGATTGGATTAGCAAAGGCATGCAAAGTCCTAAGAC

TAGCCAATAATCCAGATATAGTAAAGGTTATCAAGAAAATTGGACATTATCT

CAAGATGAATATCACGGTACCAGAGGATTACATCAACGGGTTTATTCGGGCC

AACAATACCTTCCTCTATCAGCTAGTTTTTGATCCCATCAAAAGGAAACTTAT

TCCTCTGAACGCCTATGAAGATGATGTTGATCCTGAAACACTAAGCTACGCTG

GGCAATATGTTGATGATTCCATAGCTCTTCAAATAGCACTTGGAAATAAAGA

TATAAATACTTTTGAACAGATCGATGACTACAATCCAGACACTGCTATGCCTG

CCCATTCAAGAAGTCATAGTTGGGATGACAAAACATGTCAAAAGTCAGCTAA

TGTTAGCAGCATTTGGCATAGGAATTACTCTCCCAGACCAGAGTCGGGTACT

GTTTCAGATGCCCCACAATTGAAGGAAAATCCAAGTACTGTGGGAGTGGAAC

GAGTGATTAGTACTAAAGGGTTAAATCTCCCAAGGAAATCATCCATTGTGAA

AAGACCAAGAAGTGCAGAGCTGTCAGAAGATGACCTGTTGAGTCAGTATTCT

CTTTCATTTACGAAGAAGACCAAGAAAAATAGCTCTGAAGGCAATAAATCAT

TGAGCTTTTCTGAAGTGTTTGTGCCTGACCTGGTAAATGGACCTACTAACAAA

AAGAGTGTAAGCACTCCACCTAGGACGAGAAATAAATTTGCAACATTTTTAC

AAAGGAAAAATGAAGAAAGTGGTGCAGTTGTGGTTCCAGGGACCAGAAGCA

GGTTTTTTTGCAGTTCAGATTCTACTGACTGTGTATCAAACAAAGTGAGCATC

CAGCCTCTGGATGAAACTGCTGTCACAGATAAAGAGAACAATCTGCATGAAT

CAGAGTATGGAGACCAAGAAGGCAAGAGACTGGTTGACACAGATGTAGCAC

GTAATTCAAGTGATGACATTCCGAATAATCATATTCCAGGTGATCATATTCCA

GACAAGGCAACAGTGTTTACAGATGAAGAGTCCTACTCTTTTGAGAGCAGCA

AATTTACAAGGACCATTTCACCACCCACTTTGGGAACACTAAGAAGTTGTTTT

AGTTGGTCTGGAGGTCTTGGAGATTTTTCAAGAACGCCGAGCCCCTCTCCAAG

CACAGCATTGCAGCAGTTCCGAAGAAAGAGCGATTCCCCCACCTCTTTGCCT

GAGAATAATATGTCTGATGTGTCGCAGTTAAAGAGCGAGGAGTCCAGTGACG

ATGAGTCTCATCCCTTACGAGAAGAGGCATGTTCTTCACAGTCCCAGGAAAG

TGGAGAATTCTCACTGCAGAGTTCAAATGCATCAAAGCTTTCTCAGTGCTCTA

GTAAGGACTCTGATTCAGAGGAATCTGATTGCAATATTAAGTTACTTGACAGT

CAAAGTGACCAGACCTCCAAGCTACGTTTATCTCATTTCTCAAAAAAAGACA

CACCTCTAAGGAACAAGGTTCCTGGGCTATATAAGTCCAGTTCTGCAGACTCT CTTTCTACAACCAAGATCAAACCTCTAGGACCTGCCAGAGCCAGTGGGCTGA GCAAGAAGCCGGCAAGCATCCAGAAGAGAAAGCATCATAATGCCGAGAACA AGCCGGGGTTACAGATCAAACTCAATGAGCTCTGGAAAAACTTTGGATTTAA AAAATTCTGA

Human EXO Protein Sequence, Variant 3 (SEQ ID NO: 77)

MGIQGLLQFIKEASEPIHVRKYKGQVVAVDTYCWLHKGAIACAEKLAKGEPTDR YVGFCMKFVNMLLSHGIKPILVFDGCTLPSKKEVERSRRERRQANLLKGKQLLR

EGKVSEARECFTRSINITHAMAHKVIKAARSQGVDCLVAPYEADAQLAYLNKAG IVQAIITEDSDLLAFGCKKVILKMDQFGNGLEIDQARLGMCRQLGDVFTEEKFRY MCILSGCDYLSSLRGIGLAKACKVLRLANNPDIVKVIKKIGHYLKMNITVPEDYIN GFIRANNTFLYQLVFDPIKRKLIPLNAYEDDVDPETLSYAGQYVDDSIALQIALGN KDINTFEQIDDYNPDTAMPAHSRSHSWDDKTCQKSANVSSIWHRNYSPRPESGT VSDAPQLKENPSTVGVERVISTKGLNLPRKSSIVKRPRSAELSEDDLLSQYSLSFT KKTKKNSSEGNKSLSFSEVFVPDLVNGPTNKKSVSTPPRTRNKFATFLQRKNEES GAVVVPGTRSRFFCSSDSTDCVSNKVSIQPLDETAVTDKENNLHESEYGDQEGK RLVDTD VARNS SDDIPNNHIPGDHIPDKATVFTDEES YSFES SKFTRTISPPTLGTL

RSCFSWSGGLGDFSRTPSPSPSTALQQFRRKSDSPTSLPENNMSDVSQLKSEESSD DESHPLREEACSSQSQESGEFSLQSSNASKLSQCSSKDSDSEESDCNIKLLDSQSD QTSKLRLSHFSKKDTPLRNKVPGLYKSSSADSLSTTKIKPLGPARASGLSKKPASI QKRKHHNAENKPGLQIKLNELWKNFGFKKF

Human DNA2 cDNA Sequence (SEQ ID NO: 78)

ATGGAGCAGCTGAACGAACTGGAGCTGCTGATGGAGAAGAGTTTTTGGGAGG AGGCGGAGCTGCCGGCGGAGCTATTTCAGAAGAAAGTGGTAGCTTCCTTTCC AAGAACAGTTCTGAGCACAGGAATGGATAACCGGTACCTGGTGTTGGCAGTC AATACTGTACAGAACAAAGAGGGAAACTGTGAAAAGCGCCTGGTCATCACTG CTTCACAGTCACTAGAAAATAAAGAACTATGCATCCTTAGGAATGACTGGTG TTCTGTTCCAGTAGAGCCAGGAGATATCATTCATTTGGAGGGAGACTGCACA TCTGACACTTGGATAATAGATAAAGATTTTGGATATTTGATTCTGTATCCAGA CATGCTGATTTCTGGCACCAGCATAGCCAGTAGTATTCGATGTATGAGAAGA GCTGTCCTGAGTGAAACTTTTAGGAGCTCTGATCCAGCCACACGCCAAATGCT

AATTGGTACGGTTCTCCATGAGGTGTTTCAAAAAGCCATAAATAATAGCTTTG CCCCAGAAAAGCTACAAGAACTTGCTTTTCAAACAATTCAAGAAATAAGACA TTTGAAGGAAATGTACCGCTTAAATCTAAGTCAAGATGAAATAAAACAAGAA GTAGAGGACTATCTTCCTTCGTTTTGTAAATGGGCAGGAGATTTCATGCATAA AAACACTTCGACTGACTTCCCTCAGATGCAGCTCTCTCTGCCAAGTGATAATA GTAAGGATAATTCAACATGTAACATTGAAGTCGTGAAACCAATGGATATTGA AGAAAGCATTTGGTCCCCTAGGTTTGGATTGAAAGGCAAAATAGATGTTACA GTTGGTGTGAAAATACATCGAGGGTATAAAACAAAATACAAGATAATGCCGC TGGAACTTAAAACTGGCAAAGAATCAAATTCTATTGAACACCGTAGTCAGGT

TGTTCTGTACACTCTACTAAGCCAAGAGAGAAGAGCTGATCCAGAGGCTGGC TTGCTTCTCTACCTCAAGACTGGTCAGATGTACCCTGTGCCTGCCAACCATCT AGATAAAAGAGAATTATTAAAGCTAAGAAACCAGATGGCATTCTCATTGTTT

CACCGTATTAGCAAATCTGCTACTAGACAGAAGACACAGCTTGCTTCTTTGCC

ACAAATAATTGAGGAAGAGAAAACTTGTAAATATTGTTCACAAATTGGCAAT

TGTGCTCTTTATAGCAGAGCAGTTGAACAACAGATGGATTGTAGTTCAGTCCC

AATTGTGATGCTGCCCAAAATAGAAGAAGAAACCCAGCATCTGAAGCAAAC

ACACTTAGAATATTTCAGCCTTTGGTGTCTAATGTTAACCCTGGAGTCACAAT

CGAAGGATAATAAAAAGAATCACCAAAATATCTGGCTAATGCCTGCTTCGGA

AATGGAGAAGAGTGGCAGTTGCATTGGAAACCTGATTAGAATGGAACATGTA

AAGATAGTTTGTGATGGGCAATATTTACATAATTTCCAATGTAAACATGGTGC

CATACCTGTCACAAATCTAATGGCAGGTGACAGAGTTATTGTAAGTGGAGAA

GAAAGGTCACTGTTTGCTTTGTCTAGAGGATATGTGAAGGAGATTAACATGA

CAACAGTAACTTGTTTATTAGACAGAAACTTGTCGGTCCTTCCAGAATCAACT

TTGTTCAGATTAGACCAAGAAGAAAAAAATTGTGATATAGATACCCCATTAG

GAAATCTTTCCAAATTGATGGAAAACACGTTTGTCAGCAAAAAACTTCGAGA

TTTAATTATTGACTTTCGTGAACCTCAGTTTATATCCTACCTTAGTTCTGTTCT

TCCACATGATGCAAAGGATACAGTTGCCTGCATTCTAAAGGGTTTGAATAAG

CCTCAGAGGCAAGCGATGAAAAAGGTACTTCTTTCAAAAGACTACACACTCA

TCGTGGGTATGCCTGGGACAGGAAAAACAACTACGATATGTACTCTCGTAAG

AATTCTCTACGCCTGTGGTTTTAGCGTTTTGTTGACCAGCTATACACACTCTGC

TGTTGACAATATTCTTTTGAAGTTAGCCAAGTTTAAAATAGGATTTTTGCGTT

TGGGTCAGATTCAGAAGGTTCATCCAGCTATCCAGCAATTTACAGAGCAAGA

AATTTGCAGATCAAAGTCCATTAAATCCTTAGCTCTTCTAGAAGAACTCTACA

ATAGTCAACTTATAGTTGCAACAACATGTATGGGAATAAACCATCCAATATTT

TCCCGTAAAATTTTTGATTTTTGTATTGTGGATGAAGCCTCTCAAATTAGCCA

ACCAATTTGTCTGGGCCCCCTTTTTTTTTCACGGAGATTTGTGTTAGTGGGGG

ACCATCAGCAGCTTCCTCCCCTGGTGCTAAACCGTGAAGCAAGAGCTCTTGG

CATGAGTGAAAGCTTATTCAAGAGGCTGGAGCAGAATAAGAGTGCTGTTGTA

CAGTTAACCGTGCAGTACAGAATGAACAGTAAAATTATGTCCTTAAGTAATA

AGCTGACCTATGAGGGCAAGCTGGAGTGTGGATCAGACAAAGTGGCCAATGC

AGTGATAAACCTACGTCACTTTAAAGATGTGAAGCTGGAACTGGAATTTTAT

GCTGACTATTCTGATAATCCTTGGTTGATGGGAGTATTTGAACCCAACAATCC

TGTTTGTTTCCTTAATACAGACAAGGTTCCAGCGCCAGAACAAGTTGAAAAA

GGTGGTGTGAGCAATGTAACAGAAGCCAAACTCATAGTTTTCCTAACCTCCA

TTTTTGTTAAGGCTGGATGCAGTCCCTCTGATATTGGTATTATTGCACCGTAC

AGGCAGCAATTAAAGATCATCAATGATTTATTGGCACGTTCTATTGGGATGGT

CGAAGTTAATACAGTAGACAAATACCAAGGAAGGGACAAAAGTATTGTCCTA

GTATCTTTTGTTAGAAGTAATAAGGATGGAACTGTTGGTGAACTCTTGAAAG

ATTGGCGACGTCTTAATGTTGCTATAACCAGAGCCAAACATAAACTGATTCTT

CTGGGGTGTGTGCCCTCACTAAATTGCTATCCTCCTTTGGAGAAGCTGCTTAA

TCATTTAAACTCAGAAAAATTAATCATTGATCTTCCATCAAGAGAACATGAA

AGTCTTTGCCACATATTGGGTGACTTTCAAAGAGAATAA Human DNA2 Protein Sequence (SEQ ID NO: 79)

MEQLNELELLMEKSFWEEAELPAELFQKKVVASFPRTVLSTGMDNRYLVLAVN

TVQNKEGNCEKRLVITASQSLENKELCILRNDWCSVPVEPGDIIHLEGDCTSDTWI

IDKDFGYLILYPDMLISGTSIASSIRCMRRAVLSETFRSSDPATRQMLIGTVLHEVF

QKAINNSFAPEKLQELAFQTIQEIRHLKEMYRLNLSQDEIKQEVEDYLPSFCKWA

GDFMHKNTSTDFPQMQLSLPSDNSKDNSTCNIEVVKPMDIEESIWSPRFGLKGKI

DVTVGVKIHRGYKTKYKIMPLELKTGKESNSIEHRSQVVLYTLLSQERRADPEAG

LLLYLKTGQMYPVPANHLDKRELLKLRNQMAFSLFHRISKSATRQKTQLASLPQI

IEEEKTCKYCSQIGNCALYSRAVEQQMDCSSVPIVMLPKIEEETQHLKQTHLEYFS

LWCLMLTLESQSKDNKKNHQNIWLMPASEMEKSGSCIGNLIRMEHVKIVCDGQ

YLHNFQCKHGAIPVTNLMAGDRVIVSGEERSLFALSRGYVKEINMTTVTCLLDR

NLSVLPESTLFRLDQEEKNCDIDTPLGNLSKLMENTFVSKKLRDLIIDFREPQFISY

LSSVLPHDAKDTVACILKGLNKPQRQAMKKVLLSKDYTLIVGMPGTGKTTTICT

LVRILYACGFSVLLTSYTHSAVDNILLKLAKFKIGFLRLGQIQKVHPAIQQFTEQEI

CRSKSIKSLALLEELYNSQLIVATTCMGINHPIFSRKIFDFCIVDEASQISQPICLG PL

FFSRRFVLVGDHQQLPPLVLNREARALGMSESLFKRLEQNKSAVVQLTVQYRM

NSKIMSLSNKLTYEGKLECGSDKVANAVINLRHFKDVKLELEFYADYSDNPWLM

GVFEPNNPVCFLNTDKVPAPEQVEKGGVSNVTEAKLIVFLTSIFVKAGCSPSDIGII

APYRQQLKIINDLLARSIGMVEVNTVDKYQGRDKSIVLVSFVRSNKDGTVGELLK

DWRRLNVAITRAKHKLILLGCVPSLNCYPPLEKLLNHLNSEKLIIDLPSREHESLC

HILGDFQRE

Human RBBP8 cDNA Sequence, Variant 1 (SEQ ID NO: 80)

ATGAACATCTCGGGAAGCAGCTGTGGAAGCCCTAACTCTGCAGATACATCTA

GTGACTTTAAGGACCTTTGGACAAAACTAAAAGAATGTCATGATAGAGAAGT

ACAAGGTTTACAAGTAAAAGTAACCAAGCTAAAACAGGAACGAATCTTAGAT

GCACAAAGACTAGAAGAATTCTTCACCAAAAATCAACAGCTGAGGGAACAG

CAGAAAGTCCTTCATGAAACCATTAAAGTTTTAGAAGATCGGTTAAGAGCAG

GCTTATGTGATCGCTGTGCAGTAACTGAAGAACATATGCGGAAAAAACAGCA

AGAGTTTGAAAATATCCGGCAGCAGAATCTTAAACTTATTACAGAACTTATG

AATGAAAGGAATACTCTACAGGAAGAAAATAAAAAGCTTTCTGAACAACTCC

AGCAGAAAATTGAGAATGATCAACAGCATCAAGCAGCTGAGCTTGAATGTGA

GGAAGACGTTATTCCAGATTCACCGATAACAGCCTTCTCATTTTCTGGCGTTA

ACCGGCTACGAAGAAAGGAGAACCCCCATGTCCGATACATAGAACAAACAC

ATACTAAATTGGAGCACTCTGTGTGTGCAAATGAAATGAGAAAAGTTTCCAA

GTCTTCAACTCATCCACAACATAATCCTAATGAAAATGAAATTCTAGTAGCTG

ACACTTATGACCAAAGTCAATCTCCAATGGCCAAAGCACATGGAACAAGCAG

CTATACCCCTGATAAGTCATCTTTTAATTTAGCTACAGTTGTTGCTGAAACAC

TTGGACTTGGTGTTCAAGAAGAATCTGAAACTCAAGGTCCCATGAGCCCCCTT

GGTGATGAGCTCTACCACTGTCTGGAAGGAAATCACAAGAAACAGCCTTTTG

AGGAATCTACAAGAAATACTGAAGATAGTTTAAGATTTTCAGATTCTACTTCA

AAGACTCCTCCTCAAGAAGAATTACCTACTCGAGTGTCATCTCCTGTATTTGG

AGCTACCTCTAGTATCAAAAGTGGTTTAGATTTGAATACAAGTTTGTCCCCTT CTCTTTTACAGCCTGGGAAAAAAAAACATCTGAAAACACTCCCTTTTAGCAA CACTTGTATATCTAGATTAGAAAAAACTAGATCAAAATCTGAAGATAGTGCC CTTTTCACACATCACAGTCTTGGGTCTGAAGTGAACAAGATCATTATCCAGTC ATCTAATAAACAGATACTTATAAATAAAAATATAAGTGAATCCCTAGGTGAA CAGAATAGGACTGAGTACGGTAAAGATTCTAACACTGATAAACATTTGGAGC CCCTGAAATCATTGGGAGGCCGAACATCCAAAAGGAAGAAAACTGAGGAAG AAAGTGAACATGAAGTAAGCTGCCCCCAAGCTTCTTTTGATAAAGAAAATGC TTTCCCTTTTCCAATGGATAATCAGTTTTCCATGAATGGAGACTGTGTGATGG ATAAACCTCTGGATCTGTCTGATCGATTTTCAGCTATTCAGCGTCAAGAGAAA AGCCAAGGAAGTGAGACTTCTAAAAACAAATTTAGGCAAGTGACTCTTTATG AGGCTTTGAAGACCATTCCAAAGGGCTTTTCCTCAAGCCGTAAGGCCTCAGA

TGGCAACTGCACGTTGCCCAAAGATTCCCCAGGGGAGCCCTGTTCACAGGAA TGCATCATCCTTCAGCCCTTGAATAAATGCTCTCCAGACAATAAACCATCATT ACAAATAAAAGAAGAAAATGCTGTCTTTAAAATTCCTCTACGTCCACGTGAA AGTTTGGAGACTGAGAATGTTTTAGATGACATAAAGAGTGCTGGTTCTCATG AGCCAATAAAAATACAAACCAGGTCAGACCATGGAGGATGTGAACTTGCATC AGTTCTTCAGTTAAATCCATGTAGAACTGGTAAAATAAAGTCTCTACAAAAC AACCAAGATGTATCCTTTGAAAATATCCAGTGGAGTATAGATCCGGGAGCAG ACCTTTCTCAGTATAAAATGGATGTTACTGTAATAGATACAAAGGATGGCAG TCAGTCAAAATTAGGAGGAGAGACAGTGGACATGGACTGTACATTGGTTAGT GAAACCGTTCTCTTAAAAATGAAGAAGCAAGAGCAGAAGGGAGAAAAAAGT

TCAAATGAAGAAAGAAAAATGAATGATAGCTTGGAAGATATGTTTGATCGGA CAACACATGAAGAGTATGAATCCTGTTTGGCAGACAGTTTCTCCCAAGCAGC AGATGAAGAGGAGGAATTGTCTACTGCCACAAAGAAACTACACACTCATGGT GATAAACAAGACAAAGTCAAGCAGAAAGCGTTTGTGGAGCCGTATTTTAAAG GTGATGAAAGAGAGACTAGCTTGCAAAATTTTCCTCATATTGAGGTGGTTCG GAAAAAAGAGGAGAGAAGAAAACTGCTTGGGCACACGTGTAAGGAATGTGA AATTTATTATGCAGATATGCCAGCAGAAGAAAGAGAAAAGAAATTGGCTTCC TGCTCAAGACACCGATTCCGCTACATTCCACCCAACACACCAGAGAATTTTTG GGAAGTTGGTTTTCCTTCCACTCAGACTTGTATGGAAAGAGGTTATATTAAGG AAGATCTTGATCCTTGTCCTCGTCCAAAAAGACGTCAGCCTTACAACGCAATA

TTTTCTCCAAAAGGCAAGGAGCAGAAGACATAG

Human RBBP8 Protein Sequence, Variant 1 (SEQ ID NO: 81)

MNISGS SCGSPNS ADTS SDFKDLWTKLKECHDREVQGLQVKVTKLKQERILD AQ RLEEFFTKNQQLREQQKVLHETIKVLEDRLRAGLCDRCAVTEEHMRKKQQEFEN IRQQNLKLITELMNERNTLQEENKKLSEQLQQKIENDQQHQAAELECEEDVIPDS PITAFSFSGVNRLRRKENPHVRYIEQTHTKLEHSVCANEMRKVSKSSTHPQHNPN ENEIL VADTYDQSQSPMAKAHGTSSYTPDKSSFNLATVVAETLGLGVQEESETQ GPMSPLGDELYHCLEGNHKKQPFEESTRNTEDSLRFSDSTSKTPPQEELPTRVSSP VFGATSSIKSGLDLNTSLSPSLLQPGKKKHLKTLPFSNTCISRLEKTRSKSEDSALF THHSLGSEVNKIIIQSSNKQILINKNISESLGEQNRTEYGKDSNTDKHLEPLKSLGG RTSKRKKTEEESEHEVSCPQASFDKENAFPFPMDNQFSMNGDCVMDKPLDLSDR FSAIQRQEKSQGSETSKNKFRQVTLYEALKTIPKGFSSSRKASDGNCTLPKDSPGE PCSQECIILQPLNKCSPDNKPSLQIKEENAVFKIPLRPRESLETENVLDDIKSAGSHE

PIKIQTRSDHGGCELASVLQLNPCRTGKIKSLQNNQDVSFENIQWSIDPGADLSQY

KMDVTVIDTKDGSQSKLGGETVDMDCTLVSETVLLKMKKQEQKGEKSSNEERK

MNDSLEDMFDRTTHEEYESCLADSFSQAADEEEELSTATKKLHTHGDKQDKVK

QKAFVEPYFKGDERETSLQNFPHIEVVRKKEERRKLLGHTCKECEIYYADMPAEE

REKKLASCSRHRFRYIPPNTPENFWEVGFPSTQTCMERGYIKEDLDPCPRPKRRQ

PYNAIFSPKGKEQKT

Human RBBP8 cDNA Sequence, Variant 2 (SEQ ID NO: 82)

ATGAACATCTCGGGAAGCAGCTGTGGAAGCCCTAACTCTGCAGATACATCTA

GTGACTTTAAGGACCTTTGGACAAAACTAAAAGAATGTCATGATAGAGAAGT

ACAAGGTTTACAAGTAAAAGTAACCAAGCTAAAACAGGAACGAATCTTAGAT

GCACAAAGACTAGAAGAATTCTTCACCAAAAATCAACAGCTGAGGGAACAG

CAGAAAGTCCTTCATGAAACCATTAAAGTTTTAGAAGATCGGTTAAGAGCAG

GCTTATGTGATCGCTGTGCAGTAACTGAAGAACATATGCGGAAAAAACAGCA

AGAGTTTGAAAATATCCGGCAGCAGAATCTTAAACTTATTACAGAACTTATG

AATGAAAGGAATACTCTACAGGAAGAAAATAAAAAGCTTTCTGAACAACTCC

AGCAGAAAATTGAGAATGATCAACAGCATCAAGCAGCTGAGCTTGAATGTGA

GGAAGACGTTATTCCAGATTCACCGATAACAGCCTTCTCATTTTCTGGCGTTA

ACCGGCTACGAAGAAAGGAGAACCCCCATGTCCGATACATAGAACAAACAC

ATACTAAATTGGAGCACTCTGTGTGTGCAAATGAAATGAGAAAAGTTTCCAA

GTCTTCAACTCATCCACAACATAATCCTAATGAAAATGAAATTCTAGTAGCTG

ACACTTATGACCAAAGTCAATCTCCAATGGCCAAAGCACATGGAACAAGCAG

CTATACCCCTGATAAGTCATCTTTTAATTTAGCTACAGTTGTTGCTGAAACAC

TTGGACTTGGTGTTCAAGAAGAATCTGAAACTCAAGGTCCCATGAGCCCCCTT

GGTGATGAGCTCTACCACTGTCTGGAAGGAAATCACAAGAAACAGCCTTTTG

AGGAATCTACAAGAAATACTGAAGATAGTTTAAGATTTTCAGATTCTACTTCA

AAGACTCCTCCTCAAGAAGAATTACCTACTCGAGTGTCATCTCCTGTATTTGG

AGCTACCTCTAGTATCAAAAGTGGTTTAGATTTGAATACAAGTTTGTCCCCTT

CTCTTTTACAGCCTGGGAAAAAAAAACATCTGAAAACACTCCCTTTTAGCAA

CACTTGTATATCTAGATTAGAAAAAACTAGATCAAAATCTGAAGATAGTGCC

CTTTTCACACATCACAGTCTTGGGTCTGAAGTGAACAAGATCATTATCCAGTC

ATCTAATAAACAGATACTTATAAATAAAAATATAAGTGAATCCCTAGGTGAA

CAGAATAGGACTGAGTACGGTAAAGATTCTAACACTGATAAACATTTGGAGC

CCCTGAAATCATTGGGAGGCCGAACATCCAAAAGGAAGAAAACTGAGGAAG

AAAGTGAACATGAAGTAAGCTGCCCCCAAGCTTCTTTTGATAAAGAAAATGC

TTTCCCTTTTCCAATGGATAATCAGTTTTCCATGAATGGAGACTGTGTGATGG

ATAAACCTCTGGATCTGTCTGATCGATTTTCAGCTATTCAGCGTCAAGAGAAA

AGCCAAGGAAGTGAGACTTCTAAAAACAAATTTAGGCAAGTGACTCTTTATG

AGGCTTTGAAGACCATTCCAAAGGGCTTTTCCTCAAGCCGTAAGGCCTCAGA

TGGCAACTGCACGTTGCCCAAAGATTCCCCAGGGGAGCCCTGTTCACAGGAA

TGCATCATCCTTCAGCCCTTGAATAAATGCTCTCCAGACAATAAACCATCATT

ACAAATAAAAGAAGAAAATGCTGTCTTTAAAATTCCTCTACGTCCACGTGAA

AGTTTGGAGACTGAGAATGTTTTAGATGACATAAAGAGTGCTGGTTCTCATG AGCCAATAAAAATACAAACCAGGTCAGACCATGGAGGATGTGAACTTGCATC AGTTCTTCAGTTAAATCCATGTAGAACTGGTAAAATAAAGTCTCTACAAAAC AACCAAGATGTATCCTTTGAAAATATCCAGTGGAGTATAGATCCGGGAGCAG ACCTTTCTCAGTATAAAATGGATGTTACTGTAATAGATACAAAGGATGGCAG TCAGTCAAAATTAGGAGGAGAGACAGTGGACATGGACTGTACATTGGTTAGT GAAACCGTTCTCTTAAAAATGAAGAAGCAAGAGCAGAAGGGAGAAAAAAGT TCAAATGAAGAAAGAAAAATGAATGATAGCTTGGAAGATATGTTTGATCGGA CAACACATGAAGAGTATGAATCCTGTTTGGCAGACAGTTTCTCCCAAGCAGC AGATGAAGAGGAGGAATTGTCTACTGCCACAAAGAAACTACACACTCATGGT GATAAACAAGACAAAGTCAAGCAGAAAGCGTTTGTGGAGCCGTATTTTAAAG GTGATGAAAGTATTATGCAGATATGCCAGCAGAAGAAAGAGAAAAGAAATT GGCTTCCTGCTCAAGACACCGATTCCGCTACATTCCACCCAACACACCAGAG AATTTTTGGGAAGTTGGTTTTCCTTCCACTCAGACTTGTATGGAAAGAGGTTA TATTAAGGAAGATCTTGATCCTTGTCCTCGTCCAAAAAGACGTCAGCCTTACA ACGCAATATTTTCTCCAAAAGGCAAGGAGCAGAAGACATAGACGTTGA

Human RBBP8 Protein Sequence, Variant 2 (SEQ ID NO: 83)

MNISGS SCGSPNS ADTS SDFKDLWTKLKECHDREVQGLQVKVTKLKQERILD AQ RLEEFFTKNQQLREQQKVLHETIKVLEDRLRAGLCDRCAVTEEHMRKKQQEFEN IRQQNLKLITELMNERNTLQEENKKLSEQLQQKIENDQQHQAAELECEEDVIPDS PITAFSFSGVNRLRRKENPHVRYIEQTHTKLEHSVCANEMRKVSKSSTHPQHNPN ENEIL VADTYDQSQSPMAKAHGTSSYTPDKSSFNLATVVAETLGLGVQEESETQ GPMSPLGDELYHCLEGNHKKQPFEESTRNTEDSLRFSDSTSKTPPQEELPTRVSSP VFGATSSIKSGLDLNTSLSPSLLQPGKKKHLKTLPFSNTCISRLEKTRSKSEDSALF THHSLGSEVNKIIIQSSNKQILINKNISESLGEQNRTEYGKDSNTDKHLEPLKSLGG RTSKRKKTEEESEHEVSCPQASFDKENAFPFPMDNQFSMNGDCVMDKPLDLSDR F S AIQRQEKSQGSETSKNKFRQ VTLYEALKTIPKGF S S SRKASDGNCTLPKDSPGE PCSQECIILQPLNKCSPDNKPSLQIKEENAVFKIPLRPRESLETENVLDDIKSAGSHE PIKIQTRSDHGGCELASVLQLNPCRTGKIKSLQNNQDVSFENIQWSIDPGADLSQY KMDVTVIDTKDGSQSKLGGETVDMDCTLVSETVLLKMKKQEQKGEKSSNEERK MNDSLEDMFDRTTHEEYESCLADSFSQAADEEEELSTATKKLHTHGDKQDKVK QKAFVEPYFKGDESIMQICQQKKEKRNWLPAQDTDSATFHPTHQRIFGKLVFLPL RLVWKEVILRKILILVLVQKDVSLTTQYFLQKARSRRHRR

Human MRE11 cDNA Sequence, Variant 1 (SEQ ID NO: 84)

ATGAGTACTGCAGATGCACTTGATGATGAAAACACATTTAAAATATTAGTTG CAACAGATATTCATCTTGGATTTATGGAGAAAGATGCAGTCAGAGGAAATGA TACGTTTGTAACACTCGATGAAATTTTAAGACTTGCCCAGGAAAATGAAGTG GATTTTATTTTGTTAGGTGGTGATCTTTTTCATGAAAATAAGCCCTCAAGGAA AACATTACATACCTGCCTCGAGTTATTAAGAAAATATTGTATGGGTGATCGGC CTGTCCAGTTTGAAATTCTCAGTGATCAGTCAGTCAACTTTGGTTTTAGTAAG TTTCCATGGGTGAACTATCAAGATGGCAACCTCAACATTTCAATTCCAGTGTT TAGTATTCATGGCAATCATGACGATCCCACAGGGGCAGATGCACTTTGTGCCT TGGACATTTTAAGTTGTGCTGGATTTGTAAATCACTTTGGACGTTCAATGTCT GTGGAGAAGATAGACATTAGTCCGGTTTTGCTTCAAAAAGGAAGCACAAAGA TTGCGCTATATGGTTTAGGATCCATTCCAGATGAAAGGCTCTATCGAATGTTT GTCAATAAAAAAGTAACAATGTTGAGACCAAAGGAAGATGAGAACTCTTGGT TTAACTTATTTGTGATTCATCAGAACAGGAGTAAACATGGAAGTACTAACTTC

ATTCCAGAACAATTTTTGGATGACTTCATTGATCTTGTTATCTGGGGCCATGA ACATGAGTGTAAAATAGCTCCAACCAAAAATGAACAACAGCTGTTTTATATC TCACAACCTGGAAGCTCAGTGGTTACTTCTCTTTCCCCAGGAGAAGCTGTAAA GAAACATGTTGGTTTGCTGCGTATTAAAGGGAGGAAGATGAATATGCATAAA ATTCCTCTTCACACAGTGCGGCAGTTTTTCATGGAGGATATTGTTCTAGCTAA

TCATCCAGACATTTTTAACCCAGATAATCCTAAAGTAACCCAAGCCATACAA AGCTTCTGTTTGGAGAAGATTGAAGAAATGCTTGAAAATGCTGAACGGGAAC GTCTGGGTAATTCTCACCAGCCAGAGAAGCCTCTTGTACGACTGCGAGTGGA CTATAGTGGAGGTTTTGAACCTTTCAGTGTTCTTCGCTTTAGCCAGAAATTTG TGGATCGGGTAGCTAATCCAAAAGACATTATCCATTTTTTCAGGCATAGAGA

ACAAAAGGAAAAAACAGGAGAAGAGATCAACTTTGGGAAACTTATCACAAA GCCTTCAGAAGGAACAACTTTAAGGGTAGAAGATCTTGTAAAACAGTACTTT CAAACCGCAGAGAAGAATGTGCAGCTCTCACTGCTAACAGAAAGAGGGATG GGTGAAGCAGTACAAGAATTTGTGGACAAGGAGGAGAAAGATGCCATTGAG GAATTAGTGAAATACCAGTTGGAAAAAACACAGCGATTTCTTAAAGAACGTC

ATATTGATGCCCTCGAAGACAAAATCGATGAGGAGGTACGTCGTTTCAGAGA AACCAGACAAAAAAATACTAATGAAGAAGATGATGAAGTCCGTGAGGCTAT GACCAGGGCCAGAGCACTCAGATCTCAGTCAGAGGAGTCTGCTTCTGCCTTT AGTGCTGATGACCTTATGAGTATAGATTTAGCAGAACAGATGGCTAATGACT CTGATGATAGCATCTCAGCAGCAACCAACAAAGGAAGAGGCCGAGGAAGAG

GTCGAAGAGGTGGAAGAGGGCAGAATTCAGCATCGAGAGGAGGGTCTCAAA GAGGAAGAGCAGACACTGGTCTGGAGACTTCTACCCGTAGCAGGAACTCAAA GACTGCTGTGTCAGCATCTAGAAATATGTCTATTATAGATGCCTTTAAATCTA CAAGACAGCAGCCTTCCCGAAATGTCACTACTAAGAATTATTCAGAGGTGAT TGAGGTAGATGAATCAGATGTGGAAGAAGACATTTTTCCTACCACTTCAAAG

ACAGATCAAAGGTGGTCCAGCACATCATCCAGCAAAATCATGTCCCAGAGTC AAGTATCGAAAGGGGTTGATTTTGAATCAAGTGAGGATGATGATGATGATCC TTTTATGAACACTAGTTCTTTAAGAAGAAATAGAAGATAA

Human MRE11 Protein Sequence, Variant 1 (SEQ ID NO: 85)

MSTADALDDENTFKILVATDIHLGFMEKDAVRGNDTFVTLDEILRLAQENEVDFI LLGGDLFHENKPSRKTLHTCLELLRKYCMGDRPVQFEILSDQSVNFGFSKFPWV NYQDGNLNISIPVFSIHGNHDDPTGADALCALDILSCAGFVNHFGRSMSVEKIDIS PVLLQKGSTKIALYGLGSIPDERLYRMFVNKKVTMLRPKEDENSWFNLFVIHQN RSKHGSTNFIPEQFLDDFIDLVIWGHEHECKIAPTKNEQQLFYISQPGSSVVTSLSP

GEAVKKHVGLLRIKGRKMNMHKIPLHTVRQFFMEDIVLANHPDIFNPDNPKVTQ AIQSFCLEKIEEMLENAERERLGNSHQPEKPLVRLRVDYSGGFEPFSVLRFSQKFV DRVANPKDIIHFFRHREQKEKTGEEINFGKLITKPSEGTTLRVEDLVKQYFQTAEK NVQLSLLTERGMGEAVQEFVDKEEKDAIEELVKYQLEKTQRFLKERHIDALEDKI DEEVRRFRETRQKNTNEEDDEVREAMTRARALRSQSEESASAFSADDLMSIDLA

EQMANDSDDSISAATNKGRGRGRGRRGGRGQNSASRGGSQRGRADTGLETSTR

SRNSKTAVSASRNMSIIDAFKSTRQQPSRNVTTKNYSEVIEVDESDVEEDIFPTTS

KTDQRWS STS S SKIMSQSQ VSKGVDFES SEDDDDDPFMNTSSLRRNRR

Human MRE11 cDNA Sequence, Variant 2 (SEQ ID NO: 86)

ATGAGTACTGCAGATGCACTTGATGATGAAAACACATTTAAAATATTAGTTG

CAACAGATATTCATCTTGGATTTATGGAGAAAGATGCAGTCAGAGGAAATGA

TACGTTTGTAACACTCGATGAAATTTTAAGACTTGCCCAGGAAAATGAAGTG

GATTTTATTTTGTTAGGTGGTGATCTTTTTCATGAAAATAAGCCCTCAAGGAA

AACATTACATACCTGCCTCGAGTTATTAAGAAAATATTGTATGGGTGATCGGC

CTGTCCAGTTTGAAATTCTCAGTGATCAGTCAGTCAACTTTGGTTTTAGTAAG

TTTCCATGGGTGAACTATCAAGATGGCAACCTCAACATTTCAATTCCAGTGTT

TAGTATTCATGGCAATCATGACGATCCCACAGGGGCAGATGCACTTTGTGCCT

TGGACATTTTAAGTTGTGCTGGATTTGTAAATCACTTTGGACGTTCAATGTCT

GTGGAGAAGATAGACATTAGTCCGGTTTTGCTTCAAAAAGGAAGCACAAAGA

TTGCGCTATATGGTTTAGGATCCATTCCAGATGAAAGGCTCTATCGAATGTTT

GTCAATAAAAAAGTAACAATGTTGAGACCAAAGGAAGATGAGAACTCTTGGT

TTAACTTATTTGTGATTCATCAGAACAGGAGTAAACATGGAAGTACTAACTTC

ATTCCAGAACAATTTTTGGATGACTTCATTGATCTTGTTATCTGGGGCCATGA

ACATGAGTGTAAAATAGCTCCAACCAAAAATGAACAACAGCTGTTTTATATC

TCACAACCTGGAAGCTCAGTGGTTACTTCTCTTTCCCCAGGAGAAGCTGTAAA

GAAACATGTTGGTTTGCTGCGTATTAAAGGGAGGAAGATGAATATGCATAAA

ATTCCTCTTCACACAGTGCGGCAGTTTTTCATGGAGGATATTGTTCTAGCTAA

TCATCCAGACATTTTTAACCCAGATAATCCTAAAGTAACCCAAGCCATACAA

AGCTTCTGTTTGGAGAAGATTGAAGAAATGCTTGAAAATGCTGAACGGGAAC

GTCTGGGTAATTCTCACCAGCCAGAGAAGCCTCTTGTACGACTGCGAGTGGA

CTATAGTGGAGGTTTTGAACCTTTCAGTGTTCTTCGCTTTAGCCAGAAATTTG

TGGATCGGGTAGCTAATCCAAAAGACATTATCCATTTTTTCAGGCATAGAGA

ACAAAAGGAAAAAACAGGAGAAGAGATCAACTTTGGGAAACTTATCACAAA

GCCTTCAGAAGGAACAACTTTAAGGGTAGAAGATCTTGTAAAACAGTACTTT

CAAACCGCAGAGAAGAATGTGCAGCTCTCACTGCTAACAGAAAGAGGGATG

GGTGAAGCAGTACAAGAATTTGTGGACAAGGAGGAGAAAGATGCCATTGAG

GAATTAGTGAAATACCAGTTGGAAAAAACACAGCGATTTCTTAAAGAACGTC

ATATTGATGCCCTCGAAGACAAAATCGATGAGGAGGTACGTCGTTTCAGAGA

AACCAGACAAAAAAATACTAATGAAGAAGATGATGAAGTCCGTGAGGCTAT

GACCAGGGCCAGAGCACTCAGATCTCAGTCAGAGGAGTCTGCTTCTGCCTTT

AGTGCTGATGACCTTATGAGTATAGATTTAGCAGAACAGATGGCTAATGACT

CTGATGATAGCATCTCAGCAGCAACCAACAAAGGAAGAGGCCGAGGAAGAG

GTCGAAGAGGTGGAAGAGGGCAGAATTCAGCATCGAGAGGAGGGTCTCAAA

GAGGAAGAGCCTTTAAATCTACAAGACAGCAGCCTTCCCGAAATGTCACTAC

TAAGAATTATTCAGAGGTGATTGAGGTAGATGAATCAGATGTGGAAGAAGAC

ATTTTTCCTACCACTTCAAAGACAGATCAAAGGTGGTCCAGCACATCATCCAG

CAAAATCATGTCCCAGAGTCAAGTATCGAAAGGGGTTGATTTTGAATCAAGT GAGGATGATGATGATGATCCTTTTATGAACACTAGTTCTTTAAGAAGAAATA

GAAGATAA

Human MRE11 Protein Sequence, Variant 2 (SEQ ID NO: 87)

MSTADALDDENTFKILVATDIHLGFMEKDAVRGNDTFVTLDEILRLAQENEVDFI LLGGDLFHENKPSRKTLHTCLELLRKYCMGDRPVQFEILSDQSVNFGFSKFPWV NYQDGNLNISIPVFSIHGNHDDPTGADALCALDILSCAGFVNHFGRSMSVEKIDIS PVLLQKGSTKIALYGLGSIPDERLYRMFVNKKVTMLRPKEDENSWFNLFVIHQN RSKHGSTNFIPEQFLDDFIDLVIWGHEHECKIAPTKNEQQLFYISQPGSSVVTSLSP GEAVKKHVGLLRIKGRKMNMHKIPLHTVRQFFMEDIVLANHPDIFNPDNPKVTQ AIQSFCLEKIEEMLENAERERLGNSHQPEKPLVRLRVDYSGGFEPFSVLRFSQKFV DRVANPKDIIHFFRHREQKEKTGEEINFGKLITKPSEGTTLRVEDLVKQYFQTAEK

NVQLSLLTERGMGEAVQEFVDKEEKDAIEELVKYQLEKTQRFLKERHIDALEDKI DEEVRRFRETRQKNTNEEDDEVREAMTRARALRSQSEESASAFSADDLMSIDLA EQMANDSDDSISAATNKGRGRGRGRRGGRGQNSASRGGSQRGRAFKSTRQQPS RNVTTKNYSEVIEVDESDVEEDIFPTTSKTDQRWSSTSSSKIMSQSQVSKGVDFES SEDDDDDPFMNTS SLRRNRR

Human MRE11 cDNA Sequence, Variant 3 (SEQ ID NO: 88)

ATGAGTACTGCAGATGCACTTGATGATGAAAACACATTTAAAATATTAGTTG CAACAGATATTCATCTTGGATTTATGGAGAAAGATGCAGTCAGAGGAAATGA TACGTTTGTAACACTCGATGAAATTTTAAGACTTGCCCAGGAAAATGAAGTG GATTTTATTTTGTTAGGTGGTGATCTTTTTCATGAAAATAAGCCCTCAAGGAA AACATTACATACCTGCCTCGAGTTATTAAGAAAATATTGTATGGGTGATCGGC CTGTCCAGTTTGAAATTCTCAGTGATCAGTCAGTCAACTTTGGTTTTAGTAAG TTTCCATGGGTGAACTATCAAGATGGCAACCTCAACATTTCAATTCCAGTGTT TAGTATTCATGGCAATCATGACGATCCCACAGGGGCAGATGCACTTTGTGCCT TGGACATTTTAAGTTGTGCTGGATTTGTAAATCACTTTGGACGTTCAATGTCT

GTGGAGAAGATAGACATTAGTCCGGTTTTGCTTCAAAAAGGAAGCACAAAGA TTGCGCTATATGGTTTAGGATCCATTCCAGATGAAAGGCTCTATCGAATGTTT GTCAATAAAAAAGTAACAATGTTGAGACCAAAGGAAGATGAGAACTCTTGGT TTAACTTATTTGTGATTCATCAGAACAGGAGTAAACATGGAAGTACTAACTTC ATTCCAGAACAATTTTTGGATGACTTCATTGATCTTGTTATCTGGGGCCATGA ACATGAGTGTAAAATAGCTCCAACCAAAAATGAACAACAGCTGTTTTATATC TCACAACCTGGAAGCTCAGTGGTTACTTCTCTTTCCCCAGGAGAAGCTGTAAA GAAACATGTTGGTTTGCTGCGTATTAAAGGGAGGAAGATGAATATGCATAAA ATTCCTCTTCACACAGTGCGGCAGTTTTTCATGGAGGATATTGTTCTAGCTAA TCATCCAGACATTTTTAACCCAGATAATCCTAAAGTAACCCAAGCCATACAA

AGCTTCTGTTTGGAGAAGATTGAAGAAATGCTTGAAAATGCTGAACGGGAAC GTCTGGGTAATTCTCACCAGCCAGAGAAGCCTCTTGTACGACTGCGAGTGGA CTATAGTGGAGGTTTTGAACCTTTCAGTGTTCTTCGCTTTAGCCAGAAATTTG TGGATCGGGTAGCTAATCCAAAAGACATTATCCATTTTTTCAGGCATAGAGA ACAAAAGGAAAAAACAGGAGAAGAGATCAACTTTGGGAAACTTATCACAAA GCCTTCAGAAGGAACAACTTTAAGGGTAGAAGATCTTGTAAAACAGTACTTT CAAACCGCAGAGAAGAATGTGCAGCTCTCACTGCTAACAGAAAGAGGGATG GGTGAAGCAGTACAAGAATTTGTGGACAAGGAGGAGAAAGATGCCATTGAG GAATTAGTGAAATACCAGTTGGAAAAAACACAGCGATTTCTTAAAGAACGTC ATATTGATGCCCTCGAAGACAAAATCGATGAGGAGGTACGTCGTTTCAGAGA AACCAGACAAAAAAATACTAATGAAGAAGATGATGAAGTCCGTGAGGCTAT GACCAGGGCCAGAGCACTCAGATCTCAGTCAGAGGAGTCTGCTTCTGCCTTT AGTGCTGATGACCTTATGAGTATAGATTTAGCAGAACAGATGGCTAATGACT

CTGATGATAGCATCTCAGCAGCAACCAACAAAGGAAGAGGCCGAGGAAGAG GTCGAAGAGGTGGAAGAGGGCAGAATTCAGCATCGAGAGGAGGGTCTCAAA GAGGAAGAGACACTGGTCTGGAGACTTCTACCCGTAGCAGGAACTCAAAGAC TGCTGTGTCAGCATCTAGAAATATGTCTATTATAGATGCCTTTAAATCTACAA GACAGCAGCCTTCCCGAAATGTCACTACTAAGAATTATTCAGAGGTGATTGA GGTAGATGAATCAGATGTGGAAGAAGACATTTTTCCTACCACTTCAAAGACA GATCAAAGGTGGTCCAGCACATCATCCAGCAAAATCATGTCCCAGAGTCAAG TATCGAAAGGGGTTGATTTTGAATCAAGTGAGGATGATGATGATGATCCTTTT

ATGAACACTAGTTCTTTAAGAAGAAATAGAAGATAA

Human MRE11 Protein Sequence, Variant 3 (SEQ ID NO: 89)

MSTADALDDENTFKILVATDIHLGFMEKDAVRGNDTFVTLDEILRLAQENEVDFI LLGGDLFHENKPSRKTLHTCLELLRKYCMGDRPVQFEILSDQSVNFGFSKFPWV NYQDGNLNISIPVFSIHGNHDDPTGADALCALDILSCAGFVNHFGRSMSVEKIDIS PVLLQKGSTKIALYGLGSIPDERLYRMFVNKKVTMLRPKEDENSWFNLFVIHQN RSKHGSTNFIPEQFLDDFIDLVIWGHEHECKIAPTKNEQQLFYISQPGSSVVTSLSP GEAVKKHVGLLRIKGRKMNMHKIPLHTVRQFFMEDIVLANHPDIFNPDNPKVTQ AIQSFCLEKIEEMLENAERERLGNSHQPEKPLVRLRVDYSGGFEPFSVLRFSQKFV DRVANPKDIIHFFRHREQKEKTGEEINFGKLITKPSEGTTLRVEDLVKQYFQTAEK

NVQLSLLTERGMGEAVQEFVDKEEKDAIEELVKYQLEKTQRFLKERHIDALEDKI DEEVRRFRETRQKNTNEEDDEVREAMTRARALRSQSEESASAFSADDLMSIDLA EQMANDSDDSISAATNKGRGRGRGRRGGRGQNSASRGGSQRGRDTGLETSTRS RNSKTAVSASRNMSIIDAFKSTRQQPSRNVTTKNYSEVIEVDESDVEEDIFPTTSK TDQRWSSTSSSKIMSQSQVSKGVDFESSEDDDDDPFMNTSSLRRNRR

Wildtype Human ATM (SEQ ID NO: 90)

MSLVLNDLLICCRQLEHDRATERKKEVEKFKRLIRDPETIKHLDRHSDSKQGKYLNW DAV FRFLQKYIQKETECLRIAKPNVSASTQASRQKKMQEISSLVKYFIKCANRRAPRLKCQEL LNYIMDTVKDSSNGAIYGADCSNILLKDILSVRKYWCEISQQQWLELFSVYFRLYLKPSQ DVHRVLVARI IHAVTKGCCSQTDGLNSKFLDFFSKAIQCARQEKSSSGLNHILAALTI FL KTLAVNFRIRVCELGDEILPTLLYIWTQHRLNDSLKEVIIELFQLQIYIHHPKGAKTQEK GAYESTKWRSILYNLYDLLVNEISHIGSRGKYSSGFRNIAVKENLIELMADICHQVFNED TRSLEISQSYTTTQRESSDYSVPCKRKKIELGWEVIKDHLQKSQNDFDLVPWLQIATQLI SKYPASLPNCELSPLLMILSQLLPQQRHGERTPYVLRCLTEVALCQDKRSNLESSQKSDL

LKLWNKIWCITFRGISSEQIQAENFGLLGAIIQGSLVEVDREFWKLFTGSACRPSCP AVC CLTLALTTSIVPGTVKMGIEQNMCEVNRSFSLKESIMKWLLFYQLEGDLENSTEVPPILH SNFPHLVLEKILVSLTMKNCKAAMNFFQSVPECEHHQKDKEELSFSEVEELFLQTTFDKM DFLTIVRECGIEKHQSSIGFSVHQNLKESLDRCLLGLSEQLLNNYSSEITNSETLVRCSR LLVGVLGCYCYMGVIAEEEAYKSELFQKAKSLMQCAGESITLFKNKTNEEFRIGSLRNMM QLCTRCLSNCTKKSPNKIASGFFLRLLTSKLMNDIADICKSLASFIKKPFDRGEVESMED DTNGNLMEVEDQSSMNLFNDYPDSSVSDANEPGESQSTIGAINPLAEEYLSKQDLLFLDM LKFLCLCVTTAQTNTVSFRAADIRRKLLMLIDSSTLEPTKSLHLHMYLMLLKELPGEEYP LPMEDVLELLKPLSNVCSLYRRDQDVCKTILNHVLHVVKNLGQSNMDSENTRDAQGQFLT VIGAFWHLTKERKYIFSVRMALVNCLKTLLEADPYSKWAILNVMGKDFPVNEVFTQFLAD NHHQVRMLAAESINRLFQDTKGDSSRLLKALPLKLQQTAFENAYLKAQEGMREMSHSAEN PETLDEIYNRKSVLLTLIAVVLSCSPICEKQALFALCKSVKENGLEPHLVKKVLEKVSET FGYRRLEDFMASHLDYLVLEWLNLQDTEYNLSSFPFILLNYTNIEDFYRSCYKVLIPHLV IRSHFDEVKSIANQIQEDWKSLLTDCFPKILVNILPYFAYEGTRDSGMAQQRETATKVYD MLKSENLLGKQIDHLFISNLPEIVVELLMTLHEPANSSASQSTDLCDFSGDLDPAPNPPH FPSHVIKATFAYISNCHKTKLKSILEILSKSPDSYQKILLAICEQAAETNNVYKKHRILK IYHLFVSLLLKDIKSGLGGAWAFVLRDVIYTLIHYINQRPSCIMDVSLRSFSLCCDLLSQ VCQTAVTYCKDALENHLHVIVGTLIPLVYEQVEVQKQVLDLLKYLVIDNKDNENLYITIK LLDPFPDHVVFKDLRITQQKIKYSRGPFSLLEEINHFLSVSVYDALPLTRLEGLKDLRRQ LELHKDQMVDIMRASQDNPQDGIMVKLVVNLLQLSKMAINHTGEKEVLEAVGSCLGEVGP IDFSTIAIQHSKDASYTKALKLFEDKELQWTFIMLTYLNNTLVEDCVKVRSAAVTCLKNI LATKTGHSFWEIYKMTTDPMLAYLQPFRTSRKKFLEVPRFDKENPFEGLDDINLWIPLSE NHDIWIKTLTCAFLDSGGTKCEILQLLKPMCEVKTDFCQTVLPYLIHDILLQDTNESWRN LLSTHVQGFFTSCLRHFSQTSRSTTPANLDSESEHFFRCCLDKKSQRTMLAVVDYMRRQK RPSSGTIFNDAFWLDLNYLEVAKVAQSCAAHFTALLYAEIYADKKSMDDQEKRSLAFEEG SQSTTISSLSEKSKEETGISLQDLLLEIYRSIGEPDSLYGCGGGKMLQPITRLRTYEHEA MWGKALVTYDLETAIPSSTRQAGI IQALQNLGLCHILSVYLKGLDYENKDWCPELEELHY QAAWRNMQWDHCTSVSKEVEGTSYHESLYNALQSLRDREFSTFYESLKYARVKEVEEMCK RSLESVYSLYPTLSRLQAIGELESIGELFSRSVTHRQLSEVYIKWQKHSQLLKDSDFSFQ EPIMALRTVILEILMEKEMDNSQRECIKDILTKHLVELSILARTFKNTQLPERAIFQIKQ YNSVSCGVSEWQLEEAQVFWAKKEQSLALSILKQMIKKLDASCAANNPSLKLTYTECLRV CGNWLAETCLENPAVIMQTYLEKAVEVAGNYDGESSDELRNGKMKAFLSLARFSDTQYQR IENYMKSSEFENKQALLKRAKEEVGLLREHKIQTNRYTVKVQRELELDELALRALKEDRK RFLCKAVENYINCLLSGEEHDMWVFRLCSLWLENSGVSEVNGMMKRDGMKIPTYKFLPLM YQLAARMGTKMMGGLGFHEVLNNLISRISMDHPHHTLFIILALANANRDEFLTKPEVARR SRITKNVPKQSSQLDEDRTEAANRIICTIRSRRPQMVRSVEALCDAYI ILANLDATQWKT QRKGINIPADQPITKLKNLEDVVVPTMEIKVDHTGEYGNLVTIQSFKAEFRLAGGVNLPK IIDCVGSDGKERRQLVKGRDDLRQDAVMQQVFQMCNTLLQRNTETRKRKLTICTYKVVPL SQRSGVLEWCTGTVPIGEFLVNNEDGAHKRYRPNDFSAFQCQKKMMEVQKKSFEEKYEVF MDVCQNFQPVFRYFCMEKFLDPAIWFEKRLAYTRSVATSSIVGYILGLGDRHVQNILINE QSAELVHIDLGVAFEQGKILPTPETVPFRLTRDIVDGMGITGVEGVFRRCCEKTMEVMRN SQETLLTIVEVLLYDPLFDWTMNPLKALYLQQRPEDETELHPTLNADDQECKRNLSDIDQ

SFNKVAERVLMRLQEKLKGVEEGTVLSVGGQVNLLIQQAIDPKNLSRLFPGWKAWV

Wildtype Human ATM cDNA (SEQ ID NO: 91) aggtagctgc gtggctaacg gagaaaagaa gccgtggccg cgggaggagg cgagaggagt cgggatctgc gctgcagcca ccgccgcggt tgatactact ttgaccttcc gagtgcagtg acagtgatgt gtgttctgaa attgtgaacc atgagtctag tacttaatga tctgcttatc tgctgccgtc aactagaaca tgatagagct acagaacgaa agaaagaagt tgagaaattt aagcgcctga ttcgagatcc tgaaacaatt aaacatctag atcggcattc agattccaaa caaggaaaat atttgaattg ggatgctgtt tttagatttt tacagaaata tattcagaaa gaaacagaat gtctgagaat agcaaaacca aatgtatcag cctcaacaca agcctccagg cagaaaaaga tgcaggaaat cagtagtttg gtcaaatact tcatcaaatg tgcaaacaga agagcaccta ggctaaaatg tcaagaactc ttaaattata tcatggatac agtgaaagat tcatctaatg gtgctattta cggagctgat tgtagcaaca tactactcaa agacattctt tctgtgagaa aatactggtg tgaaatatct cagcaacagt ggttagaatt gttctctgtg tacttcaggc tctatctgaa accttcacaa gatgttcata gagttttagt ggctagaata attcatgctg ttaccaaagg atgctgttct cagactgacg gattaaattc caaatttttg gacttttttt ccaaggctat tcagtgtgcg agacaagaaa agagctcttc aggtctaaat catatcttag cagctcttac tatcttcctc aagactttgg ctgtcaactt tcgaattcga gtgtgtgaat taggagatga aattcttccc actttgcttt atatttggac tcaacatagg cttaatgatt ctttaaaaga agtcattatt gaattatttc aactgcaaat ttatatccat catccgaaag gagccaaaac ccaagaaaaa ggtgcttatg aatcaacaaa atggagaagt attttataca acttatatga tctgctagtg aatgagataa gtcatatagg aagtagagga aagtattctt caggatttcg taatattgcc gtcaaagaaa atttgattga attgatggca gatatctgtc accaggtttt taatgaagat accagatcct tggagatttc tcaatcttac actactacac aaagagaatc tagtgattac agtgtccctt gcaaaaggaa gaaaatagaa ctaggctggg aagtaataaa agatcacctt cagaagtcac agaatgattt tgatcttgtg ccttggctac agattgcaac ccaattaata tcaaagtatc ctgcaagttt acctaactgt gagctgtctc cattactgat gatactatct cagcttctac cccaacagcg acatggggaa cgtacaccat atgtgttacg atgccttacg gaagttgcat tgtgtcaaga caagaggtca aacctagaaa gctcacaaaa gtcagattta ttaaaactct ggaataaaat ttggtgtatt acctttcgtg gtataagttc tgagcaaata caagctgaaa actttggctt acttggagcc ataattcagg gtagtttagt tgaggttgac agagaattct ggaagttatt tactgggtca gcctgcagac cttcatgtcc tgcagtatgc tgtttgactt tggcactgac caccagtata gttccaggaa cggtaaaaat gggaatagag caaaatatgt gtgaagtaaa tagaagcttt tctttaaagg aatcaataat gaaatggctc ttattctatc agttagaggg tgacttagaa aatagcacag aagtgcctcc aattcttcac agtaattttc ctcatcttgt actggagaaa attcttgtga gtctcactat gaaaaactgt aaagctgcaa tgaatttttt ccaaagcgtg ccagaatgtg aacaccacca aaaagataaa gaagaacttt cattctcaga agtagaagaa ctatttcttc agacaacttt tgacaagatg gactttttaa ccattgtgag agaatgtggt atagaaaagc accagtccag tattggcttc tctgtccacc agaatctcaa ggaatcactg gatcgctgtc ttctgggatt atcagaacag cttctgaata attactcatc tgagattaca aattcagaaa ctcttgtccg gtgttcacgt cttttggtgg gtgtccttgg ctgctactgt tacatgggtg taatagctga agaggaagca tataagtcag aattattcca gaaagccaag tctctaatgc aatgtgcagg agaaagtatc actctgttta aaaataagac aaatgaggaa ttcagaattg gttccttgag aaatatgatg cagctatgta cacgttgctt gagcaactgt accaagaaga gtccaaataa gattgcatct ggctttttcc tgcgattgtt aacatcaaag ctaatgaatg acattgcaga tatttgtaaa agtttagcat ccttcatcaa aaagccattt gaccgtggag aagtagaatc aatggaagat gatactaatg gaaatctaat ggaggtggag gatcagtcat ccatgaatct atttaacgat taccctgata gtagtgttag tgatgcaaac gaacctggag agagccaaag taccataggt gccattaatc ctttagctga agaatatctg tcaaagcaag atctactttt cttagacatg ctcaagttct tgtgtttgtg tgtaactact gctcagacca atactgtgtc ctttagggca gctgatattc ggaggaaatt gttaatgtta attgattcta gcacgctaga acctaccaaa tccctccacc tgcatatgta tctaatgctt ttaaaggagc ttcctggaga agagtacccc ttgccaatgg aagatgttct tgaacttctg aaaccactat ccaatgtgtg ttctttgtat cgtcgtgacc aagatgtttg taaaactatt ttaaaccatg tccttcatgt agtgaaaaac ctaggtcaaa gcaatatgga ctctgagaac acaagggatg ctcaaggaca gtttcttaca gtaattggag cattttggca tctaacaaag gagaggaaat atatattctc tgtaagaatg gccctagtaa attgccttaa aactttgctt gaggctgatc cttattcaaa atgggccatt cttaatgtaa tgggaaaaga ctttcctgta aatgaagtat ttacacaatt tcttgctgac aatcatcacc aagttcgcat gttggctgca gagtcaatca atagattgtt ccaggacacg aagggagatt cttccaggtt actgaaagca cttcctttga agcttcagca aacagctttt gaaaatgcat acttgaaagc tcaggaagga atgagagaaa tgtcccatag tgctgagaac cctgaaactt tggatgaaat ttataataga aaatctgttt tactgacgtt gatagctgtg gttttatcct gtagccctat ctgcgaaaaa caggctttgt ttgccctgtg taaatctgtg aaagagaatg gattagaacc tcaccttgtg aaaaaggttt tagagaaagt ttctgaaact tttggatata gacgtttaga agactttatg gcatctcatt tagattatct ggttttggaa tggctaaatc ttcaagatac tgaatacaac ttatcttctt ttccttttat tttattaaac tacacaaata ttgaggattt ctatagatct tgttataagg ttttgattcc acatctggtg attagaagtc attttgatga ggtgaagtcc attgctaatc agattcaaga ggactggaaa agtcttctaa cagactgctt tccaaagatt cttgtaaata ttcttcctta ttttgcctat gagggtacca gagacagtgg gatggcacag caaagagaga ctgctaccaa ggtctatgat atgcttaaaa gtgaaaactt attgggaaaa cagattgatc acttattcat tagtaattta ccagagattg tggtggagtt attgatgacg ttacatgagc cagcaaattc tagtgccagt cagagcactg acctctgtga cttttcaggg gatttggatc ctgctcctaa tccacctcat tttccatcgc atgtgattaa agcaacattt gcctatatca gcaattgtca taaaaccaag ttaaaaagca ttttagaaat tctttccaaa agccctgatt cctatcagaa aattcttctt gccatatgtg agcaagcagc tgaaacaaat aatgtttata agaagcacag aattcttaaa atatatcacc tgtttgttag tttattactg aaagatataa aaagtggctt aggaggagct tgggcctttg ttcttcgaga cgttatttat actttgattc actatatcaa ccaaaggcct tcttgtatca tggatgtgtc attacgtagc ttctcccttt gttgtgactt attaagtcag gtttgccaga cagccgtgac ttactgtaag gatgctctag aaaaccatct tcatgttatt gttggtacac ttatacccct tgtgtatgag caggtggagg ttcagaaaca ggtattggac ttgttgaaat acttagtgat agataacaag gataatgaaa acctctatat cacgattaag cttttagatc cttttcctga ccatgttgtt tttaaggatt tgcgtattac tcagcaaaaa atcaaataca gtagaggacc cttttcactc ttggaggaaa ttaaccattt tctctcagta agtgtttatg atgcacttcc attgacaaga cttgaaggac taaaggatct tcgaagacaa ctggaactac ataaagatca gatggtggac attatgagag cttctcagga taatccgcaa gatgggatta tggtgaaact agttgtcaat ttgttgcagt tatccaagat ggcaataaac cacactggtg aaaaagaagt tctagaggct gttggaagct gcttgggaga agtgggtcct atagatttct ctaccatagc tatacaacat agtaaagatg catcttatac caaggccctt aagttatttg aagataaaga acttcagtgg accttcataa tgctgaccta cctgaataac acactggtag aagattgtgt caaagttcga tcagcagctg ttacctgttt gaaaaacatt ttagccacaa agactggaca tagtttctgg gagatttata agatgacaac agatccaatg ctggcctatc tacagccttt tagaacatca agaaaaaagt ttttagaagt acccagattt gacaaagaaa acccttttga aggcctggat gatataaatc tgtggattcc tctaagtgaa aatcatgaca tttggataaa gacactgact tgtgcttttt tggacagtgg aggcacaaaa tgtgaaattc ttcaattatt aaagccaatg tgtgaagtga aaactgactt ttgtcagact gtacttccat acttgattca tgatatttta ctccaagata caaatgaatc atggagaaat ctgctttcta cacatgttca gggatttttc accagctgtc ttcgacactt ctcgcaaacg agccgatcca caacccctgc aaacttggat tcagagtcag agcacttttt ccgatgctgt ttggataaaa aatcacaaag aacaatgctt gctgttgtgg actacatgag aagacaaaag agaccttctt caggaacaat ttttaatgat gctttctggc tggatttaaa ttatctagaa gttgccaagg tagctcagtc ttgtgctgct cactttacag ctttactcta tgcagaaatc tatgcagata agaaaagtat ggatgatcaa gagaaaagaa gtcttgcatt tgaagaagga agccagagta caactatttc tagcttgagt gaaaaaagta aagaagaaac tggaataagt ttacaggatc ttctcttaga aatctacaga agtatagggg agccagatag tttgtatggc tgtggtggag ggaagatgtt acaacccatt actagactac gaacatatga acacgaagca atgtggggca aagccctagt aacatatgac ctcgaaacag caatcccctc atcaacacgc caggcaggaa tcattcaggc cttgcagaat ttgggactct gccatattct ttccgtctat ttaaaaggat tggattatga aaataaagac tggtgtcctg aactagaaga acttcattac caagcagcat ggaggaatat gcagtgggac cattgcactt ccgtcagcaa agaagtagaa ggaaccagtt accatgaatc attgtacaat gctctacaat ctctaagaga cagagaattc tctacatttt atgaaagtct caaatatgcc agagtaaaag aagtggaaga gatgtgtaag cgcagccttg agtctgtgta ttcgctctat cccacactta gcaggttgca ggccattgga gagctggaaa gcattgggga gcttttctca agatcagtca cacatagaca actctctgaa gtatatatta agtggcagaa acactcccag cttctcaagg acagtgattt tagttttcag gagcctatca tggctctacg cacagtcatt ttggagatcc tgatggaaaa ggaaatggac aactcacaaa gagaatgtat taaggacatt ctcaccaaac accttgtaga actctctata ctggccagaa ctttcaagaa cactcagctc cctgaaaggg caatatttca aattaaacag tacaattcag ttagctgtgg agtctctgag tggcagctgg aagaagcaca agtattctgg gcaaaaaagg agcagagtct tgccctgagt attctcaagc aaatgatcaa gaagttggat gccagctgtg cagcgaacaa tcccagccta aaacttacat acacagaatg tctgagggtt tgtggcaact ggttagcaga aacgtgctta gaaaatcctg cggtcatcat gcagacctat ctagaaaagg cagtagaagt tgctggaaat tatgatggag aaagtagtga tgagctaaga aatggaaaaa tgaaggcatt tctctcatta gcccggtttt cagatactca ataccaaaga attgaaaact acatgaaatc atcggaattt gaaaacaagc aagctctcct gaaaagagcc aaagaggaag taggtctcct tagggaacat aaaattcaga caaacagata cacagtaaag gttcagcgag agctggagtt ggatgaatta gccctgcgtg cactgaaaga ggatcgtaaa cgcttcttat gtaaagcagt tgaaaattat atcaactgct tattaagtgg agaagaacat gatatgtggg tattccgact ttgttccctc tggcttgaaa attctggagt ttctgaagtc aatggcatga tgaagagaga cggaatgaag attccaacat ataaattttt gcctcttatg taccaattgg ctgctagaat ggggaccaag atgatgggag gcctaggatt tcatgaagtc ctcaataatc taatctctag aatttcaatg gatcaccccc atcacacttt gtttattata ctggccttag caaatgcaaa cagagatgaa tttctgacta aaccagaggt agccagaaga agcagaataa ctaaaaatgt gcctaaacaa agctctcagc ttgatgagga tcgaacagag gctgcaaata gaataatatg tactatcaga agtaggagac ctcagatggt cagaagtgtt gaggcacttt gtgatgctta tattatatta gcaaacttag atgccactca gtggaagact cagagaaaag gcataaatat tccagcagac cagccaatta ctaaacttaa gaatttagaa gatgttgttg tccctactat ggaaattaag gtggaccaca caggagaata tggaaatctg gtgactatac agtcatttaa agcagaattt cgcttagcag gaggtgtaaa tttaccaaaa ataatagatt gtgtaggttc cgatggcaag gagaggagac agcttgttaa gggccgtgat gacctgagac aagatgctgt catgcaacag gtcttccaga tgtgtaatac attactgcag agaaacacgg aaactaggaa gaggaaatta actatctgta cttataaggt ggttcccctc tctcagcgaa gtggtgttct tgaatggtgc acaggaactg tccccattgg tgaatttctt gttaacaatg aagatggtgc tcataaaaga tacaggccaa atgatttcag tgcctttcag tgccaaaaga aaatgatgga ggtgcaaaaa aagtcttttg aagagaaata tgaagtcttc atggatgttt gccaaaattt tcaaccagtt ttccgttact tctgcatgga aaaattcttg gatccagcta tttggtttga gaagcgattg gcttatacgc gcagtgtagc tacttcttct attgttggtt acatacttgg acttggtgat agacatgtac agaatatctt gataaatgag cagtcagcag aacttgtaca tatagatcta ggtgttgctt ttgaacaggg caaaatcctt cctactcctg agacagttcc ttttagactc accagagata ttgtggatgg catgggcatt acgggtgttg aaggtgtctt cagaagatgc tgtgagaaaa ccatggaagt gatgagaaac tctcaggaaa ctctgttaac cattgtagag gtccttctat atgatccact ctttgactgg accatgaatc ctttgaaagc tttgtattta cagcagaggc cggaagatga aactgagctt caccctactc tgaatgcaga tgaccaagaa tgcaaacgaa atctcagtga tattgaccag agtttcaaca aagtagctga acgtgtctta atgagactac aagagaaact gaaaggagtg gaagaaggca ctgtgctcag tgttggtgga caagtgaatt tgctcataca gcaggccata gaccccaaaa atctcagccg acttttccca ggatggaaag cttgggtgtg atcttcagta tatgaattac cctttcattc agcctttaga aattatattt tagcctttat ttttaacctg ccaacatact ttaagtaggg attaatattt aagtgaacta ttgtgggttt ttttgaatgt tggttttaat acttgattta atcaccactc aaaaatgttt tgatggtctt aaggaacatc tctgctttca ctctttagaa ataatggtca ttcgggctgg gcgcagcggc tcacgcctgt aatcccagca ctttgggagg ccgaggtgag cggatcacaa ggtcaggagt tcgagaccag cctggccaag agaccagcct ggccagtatg gtgaaaccct gtctctacta aaaatacaaa aattagccga gcatggtggc gggcacctgt aatcccagct actcgagagg ctgaggcagg agaatctctt gaacctggga ggtgaaggtt gctgtgggcc aaaatcatgc cattgcactc cagcctgggt gacaagagcg aaactccatc tcaaaaaaaa aaaaaaaaaa acagaaacgt atttggattt ttcctagtaa gatcactcag tgttactaaa taatgaagtt gttatggaga acaaatttca aagacacagt tagtgtagtt actatttttt taagtgtgta ttaaaacttc tcattctatt ctctttatct tttaagccct tctgtactgt ccatgtatgt tatctttctg tgataacttc atagattgcc ttctagttca tgaattctct tgtcagatgt atataatctc ttttacccta tccattgggc ttcttctttc agaaattgtt tttcatttct aattatgcat catttttcag atctctgttt cttgatgtca tttttaatgt ttttttaatg ttttttatgt cactaattat tttaaatgtc tgtacttgat agacactgta atagttctat taaatttagt tcctgctgtt tatatctgtt gatttttgta tttgataggc tgttcatcca gttttgtctt tttgaaaagt gagtttattt tcagcaaggc tttatctatg ggaatcttga gtgtctgttt atgtcatatt cccagggctg ttgctgcaca caagcccatt cttattttaa tttcttggct ttagggtttc catacctgaa gtgtagcata aatactgata ggagatttcc caggccaagg caaacacact tcctcctcat ctccttgtgc tagtgggcag aatatttgat tgatgccttt ttcactgaga gtataagctt ccatgtgtcc cacctttatg gcaggggtgg aaggaggtac atttaattcc cactgcctgc ctttggcaag ccctgggttc tttgctcccc atatagatgt ctaagctaaa agccgtgggt taatgagact ggcaaattgt tccaggacag ctacagcatc agctcacata ttcacctctc tggtttttca ttcccctcat ttttttctga gacagagtct tgctctgtca cccaggctgg agtgcagtgg catgatctca gctcactgaa acctctgcct cctgggttca agcaattctc ctgcctcagc ctcccgagta gctgggacta caggcgtgtg ccaacacgcc cggctaattt tttgtatttt tattagagac ggagtttcac cgtgttagcc aggatggtct cgatcgcttg acctcgtgat ccaccctcct cggcctccca aagtgctggg attacaggtg tgagccaccg cgcccggcct cattcccctc atttttgacc gtaaggattt cccctttctt gtaagttctg ctatgtattt aaaagaatgt tttctacatt ttatccagca tttctctgtg ttctgttgga agggaagggc ttaggtatct agtttgatac ataggtagaa gtggaacatt tctctgtccc ccagctgtca tcatataaga taaacatcag ataaaaagcc acctgaaagt aaaactactg actcgtgtat tagtgagtat aatctcttct ccatccttag gaaaatgttc atcccagctg cggagattaa caaatgggtg attgagcttt ctcctcgtat ttggaccttg aaggttatat aaattttttt cttatgaaga gttggcattt ctttttattg ccaatggcag gcactcattc atatttgatc tcctcacctt cccctcccct aaaaccaatc tccagaactt tttggactat aaatttcttg gtttgacttc tggagaactg ttcagaatat tactttgcat ttcaaattac aaacttacct tggtgtatct ttttcttaca agctgcctaa atgaatattt ggtatatatt ggtagtttta ttactatagt aaatcaagga aatgcagtaa acttaaaatg tctttaagaa agccctgaaa tcttcatggg tgaaattaga aattatcaac tagataatag tatagataaa tgaatttgta gctaattctt gctagttgtt gcatccagag agctttgaat aacatcatta atctactctt tagccttgca tggtatgcta tgaggctcct gttctgttca agtattctaa tcaatggctt tgaaaagttt atcaaattta catacagatc acaagcctag gagaaataac taattcacag atgacagaat taagattata aaagattttt tttttgtaat tttagtagag acagggttgc cattgtattc cagccttggc gacagagcaa gactctgcct caaaaaaaaa aaaaaaaagg ttttggcaag ctggaactct ttctgcaaat gactaagata gaaaactgcc aaggacaaat gaggagtagt tagattttga aaatattaat catagaatag ttgttgtatg ctaagtcact gacccatatt atgtacagca tttctgatct ttactttgca agattagtga tactatccca atacactgct ggagaaatca gaatttggag aaataagttg tccaaggcaa gaagatagta aattataagt acaagtgtaa tatggacagt atctaacttg aaaagatttc aggcgaaaag aatctggggt ttgccagtca gttgctcaaa aggtcaatga aaaccaaata gtgaagctat cagagaagct aataaattat agactgcttg aacagttgtg tccagattaa gggagataat agctttccca ccctactttg tgcaggtcat acctccccaa agtgtttacc taatcagtag gttcacaaac tcttggtcat tatagtatat gcctaaaatg tatgcactta ggaatgctaa aaatttaaat atggtctaaa gcaaataaaa gcaaagagga aaaactttgg acagcgtaaa gactagaata gtcttttaaa aagaaagcca gtatattggt ttgaaatata gagatgtgtc ccaatttcaa gtattttaat tgcaccttaa tgaaattatc tattttctat agattttagt actattgaat gtattacttt actgttacct gaatttatta taaagtgttt ttgaataaat aattctaaaa gcata