{"gene":"ABRAXAS1","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":2007,"finding":"Abraxas directly binds the BRCA1 BRCT repeats through a phospho-Ser-X-X-Phe (pSXXF) motif, forming a distinct BRCA1 complex (BRCA1-A complex) that is mutually exclusive with BACH1 and CtIP complexes. Abraxas recruits the UIM-containing protein RAP80 to BRCA1, and both are required for DNA damage resistance, G2-M checkpoint control, and DNA repair. RAP80's UIM domains were sufficient for foci formation, and RAP80-Abraxas together recruit BRCA1 to DNA damage sites partly through recognition of ubiquitinated proteins.","method":"Phosphopeptide affinity proteomics, Co-IP, siRNA knockdown with DNA damage resistance, G2-M checkpoint, and foci formation readouts","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (affinity proteomics, Co-IP, functional KD assays), replicated in same year by independent labs (PMIDs 17643122, 17643121)","pmids":["17525340"],"is_preprint":false},{"year":2007,"finding":"Abraxas and BRCC36 associate through coiled-coil domains on each protein. RAP80 contains an Abraxas-interacting region (AIR) required for association of RAP80 with Abraxas, BRCA1, and BRCC36. The BRCA1-A complex is recruited to DNA damage foci via K63-linked polyubiquitin chains recognized by RAP80 UIM domains; this recruitment requires the E3 ubiquitin ligase RNF8 and the E2 enzyme Ubc13 to generate K63-polyubiquitin chains at damage sites.","method":"Co-IP, domain-deletion mapping, siRNA knockdown, foci formation assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping with Co-IP and functional siRNA knockdown, multiple orthogonal experiments in one study, replicated contextually by PMID 17525340","pmids":["18077395"],"is_preprint":false},{"year":2007,"finding":"CCDC98 (Abraxas) is a BRCA1-interacting protein that colocalizes with BRCA1 and is required for formation of BRCA1 foci in response to ionizing radiation, as well as for radiation sensitivity and damage-induced G2/M checkpoint control.","method":"Co-IP, immunofluorescence colocalization, siRNA knockdown with foci and checkpoint readouts","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent replication of PMID 17525340 findings with Co-IP and functional KD assays","pmids":["17643122"],"is_preprint":false},{"year":2007,"finding":"CCDC98 (Abraxas) mediates BRCA1's association with RAP80 within the BRCA1-RAP80 complex and controls DNA damage-induced formation of BRCA1 foci and BRCA1-dependent G2/M checkpoint activation.","method":"Co-IP, siRNA knockdown with foci and checkpoint readouts","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent replication across multiple labs using Co-IP and functional assays","pmids":["17643121"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the BRCA1-BRCT/Abraxas complex revealed that ATM-dependent phosphorylation of Abraxas Ser404 (adjacent to the pSPxF motif) induces extensive interactions through the N-terminal sequence and leads to stable BRCT dimer formation at DNA damage sites. Mutation of S404 causes deficiency in BRCA1 accumulation at damage sites and cellular sensitivity to IR. Two germline BRCA1 mutations disrupt this dimer interface.","method":"X-ray crystallography, ATM-dependent phosphorylation assay, site-directed mutagenesis, IR sensitivity and foci formation assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional assays in a single rigorous study","pmids":["26778126"],"is_preprint":false},{"year":2012,"finding":"A germline Abraxas mutation (c.1082G>A, Arg361Gln) abrogates nuclear localization of Abraxas and disrupts DNA damage response functions including BRCA1 foci formation and checkpoint control, identifying Abraxas as a breast cancer susceptibility gene.","method":"Patient mutation screening, nuclear localization assays, DNA damage response functional assays in carrier cells","journal":"Science Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cellular assays in patient-derived material, single lab","pmids":["22357538"],"is_preprint":false},{"year":2014,"finding":"Abraxas exerts tumor suppressor function through binding to BRCA1 to regulate DNA repair and maintain genome stability; homozygous and heterozygous Abraxas knockout mice exhibited decreased survival and increased tumor incidence.","method":"Mouse knockout (homozygous and heterozygous), tumor incidence monitoring, DNA repair assays","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo KO mouse model with survival and tumor phenotype, DNA repair readouts, single lab","pmids":["25066119"],"is_preprint":false},{"year":2019,"finding":"The Finnish ABRAXAS1 founder mutation (Arg361Gln), even in the heterozygous state, leads to decreased BRCA1 protein levels and reduced nuclear localization and foci formation of BRCA1 and CtIP, disturbs basal BRCA1-A complex localization, attenuates DNA damage response, and deregulates G2-M checkpoint control, acting in a dominant-negative manner on BRCA1.","method":"Patient-derived cells, Western blot, immunofluorescence, DNA repair pathway assays, G2-M checkpoint assays","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells with multiple orthogonal functional assays, single lab","pmids":["31630195"],"is_preprint":false},{"year":2021,"finding":"Abraxas limits break-induced replication (BIR) at single-ended DSBs by counteracting K63-linked ubiquitin modification and thereby restricting SLX4/MUS81 recruitment to CPT-induced damage sites. Abraxas deficiency leads to uncontrolled SLX4/MUS81 loading, excessive MRE11/CtIP/DNA2-BLM-dependent end resection, and increased RAD52- and POLD3-dependent, RAD51-independent BIR and chromosome aberrations.","method":"Abraxas KO/KD with CPT treatment, mitotic DNA synthesis assays, ubiquitin modification assays, epistasis with SLX4/MUS81/RAD52/POLD3","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple pathway components, KO functional readouts, orthogonal assays in one study","pmids":["34272385"],"is_preprint":false},{"year":2023,"finding":"Truncating germline mutations in ABRAXAS1 devoid of the C-terminal BRCA1 binding site, but retaining N-terminal interaction sites for RAP80, channel BRCA1 from the BRCA1-A complex to the BRCA1-C complex, inducing single-strand annealing (SSA). Further truncation deleting the coiled-coil region unleashes excessive DNA damage responses including SSA and NHEJ. ABRAXAS1 truncation thus de-represses multiple low-fidelity repair pathways in a dominant manner without impairing homologous recombination.","method":"Patient-derived lymphoblastoid cells, genetically manipulated mammary epithelial cells, HR reporter assay, RAD51 foci, SSA assay, NHEJ assay, PARP inhibitor sensitivity","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal repair pathway assays in patient cells plus engineered cells, single lab","pmids":["37198153"],"is_preprint":false},{"year":2022,"finding":"SUCNR1 (succinate receptor 1) directly interacts with ABRAXAS1 in gastric epithelial cells, and S. anginosus-derived succinate binding to SUCNR1 activates the PI3K/AKT signaling pathway through this interaction to promote gastric cancer progression.","method":"SUCNR1 knockdown, SUCNR1 inhibitor treatment, Co-IP (SUCNR1–ABRAXAS1 interaction), in vitro proliferation/invasion assays, in vivo gastric inflammation model","journal":"Cell Reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP interaction claim, mechanistic follow-up limited, single lab, ABRAXAS1 role in PI3K/AKT not independently validated","pmids":["41746808"],"is_preprint":false}],"current_model":"ABRAXAS1 (Abraxas/CCDC98/FAM175A) is a scaffold protein that forms the BRCA1-A complex by directly binding the BRCA1 BRCT repeats via its C-terminal pSPxF phosphomotif (phosphorylation further stabilized by ATM-dependent S404 phosphorylation inducing BRCT dimerization), bridging RAP80 (through its N-terminal AIR region) and BRCC36 (through coiled-coil domains) to assemble the complex that is recruited to K63-ubiquitin chains at DNA damage sites generated by the RNF8–Ubc13 cascade; within this complex Abraxas restrains mutagenic break-induced replication by limiting SLX4/MUS81 loading and DNA end resection, maintains G2/M checkpoint fidelity, and channels BRCA1 into high-fidelity repair, while loss-of-function mutations de-repress low-fidelity pathways (SSA, BIR, NHEJ) and cause genomic instability and tumor predisposition."},"narrative":{"mechanistic_narrative":"ABRAXAS1 (Abraxas/CCDC98/FAM175A) is a scaffold protein that nucleates the BRCA1-A complex to channel BRCA1 into high-fidelity DNA double-strand break repair and enforce the G2/M checkpoint [PMID:17525340, PMID:17643122]. It binds the BRCA1 BRCT repeats directly through a C-terminal phospho-Ser-X-X-Phe (pSXXF) motif, forming a BRCA1 complex mutually exclusive with the BACH1 and CtIP complexes, while simultaneously recruiting the UIM-containing protein RAP80 to BRCA1 [PMID:17525340]. Through coiled-coil contacts it also engages the deubiquitinase BRCC36, and RAP80's UIM domains recognize K63-linked polyubiquitin chains generated by the RNF8–Ubc13 cascade, recruiting the assembled complex to DNA damage foci [PMID:18077395]. ATM-dependent phosphorylation of Ser404, adjacent to the pSPxF motif, drives stable BRCT dimer formation and is required for BRCA1 accumulation at damage sites and IR resistance [PMID:26778126]. Beyond directing repair pathway choice, Abraxas restrains mutagenic break-induced replication by counteracting K63-ubiquitination and limiting SLX4/MUS81 loading and end resection at single-ended breaks, so that its loss de-represses low-fidelity pathways including BIR, single-strand annealing, and NHEJ [PMID:34272385, PMID:37198153]. Consistent with a genome-stabilizing tumor suppressor role, Abraxas knockout mice show increased tumor incidence [PMID:25066119], and germline ABRAXAS1 mutations — including the Finnish founder Arg361Gln allele that abrogates nuclear localization and acts dominant-negatively on BRCA1 — confer breast cancer susceptibility [PMID:22357538, PMID:31630195].","teleology":[{"year":2007,"claim":"Established Abraxas as a dedicated BRCA1 partner that defines a distinct BRCA1 complex and recruits RAP80, answering how BRCA1 is targeted to damage sites and partitioned among mutually exclusive complexes.","evidence":"Phosphopeptide affinity proteomics, Co-IP, and siRNA knockdown with DNA damage resistance, checkpoint, and foci readouts in human cells","pmids":["17525340","17643122","17643121"],"confidence":"High","gaps":["Did not resolve the ubiquitin linkage type or upstream ligase generating the recruitment signal","Structural basis of the pSXXF–BRCT interaction not defined"]},{"year":2007,"claim":"Defined the molecular architecture of the complex and its recruitment route, showing Abraxas bridges BRCC36 via coiled-coils and RAP80 via the AIR, with foci formation depending on RNF8/Ubc13-generated K63-polyubiquitin.","evidence":"Co-IP, domain-deletion mapping, siRNA knockdown, and foci formation assays","pmids":["18077395"],"confidence":"High","gaps":["Stoichiometry and assembly order of the full complex not established","Did not address how the complex influences downstream repair pathway choice"]},{"year":2012,"claim":"Linked ABRAXAS1 to human disease by identifying a germline Arg361Gln mutation that abrogates nuclear localization and disrupts the DNA damage response, establishing it as a breast cancer susceptibility gene.","evidence":"Patient mutation screening with nuclear localization and DNA damage response functional assays in carrier cells","pmids":["22357538"],"confidence":"Medium","gaps":["Single lab; penetrance and population frequency not addressed in this study","Mechanism by which the mutation blocks nuclear import not defined"]},{"year":2014,"claim":"Demonstrated in vivo tumor suppressor function, showing that Abraxas loss compromises genome stability and increases tumor incidence in mice.","evidence":"Homozygous and heterozygous knockout mice with survival monitoring, tumor incidence, and DNA repair assays","pmids":["25066119"],"confidence":"High","gaps":["Tumor spectrum and tissue specificity not fully resolved","Did not dissect which downstream repair pathway defect drives tumorigenesis"]},{"year":2016,"claim":"Provided the structural mechanism of complex stabilization, showing ATM-dependent Ser404 phosphorylation drives BRCT dimerization required for BRCA1 retention at damage sites.","evidence":"X-ray crystallography of the BRCA1-BRCT/Abraxas complex with phosphorylation assays, mutagenesis, and IR sensitivity/foci readouts","pmids":["26778126"],"confidence":"High","gaps":["Kinetics and reversibility of S404 phosphorylation in vivo not measured","Functional consequence of dimerization for downstream repair not directly tested"]},{"year":2021,"claim":"Revealed an active repair-restraining function, showing Abraxas limits break-induced replication by counteracting K63-ubiquitination and restricting SLX4/MUS81 recruitment and end resection.","evidence":"Abraxas KO/KD with CPT treatment, mitotic DNA synthesis and ubiquitin modification assays, and epistasis with SLX4/MUS81/RAD52/POLD3","pmids":["34272385"],"confidence":"High","gaps":["The deubiquitinase activity responsible (e.g. BRCC36) not directly assigned in this restraint","How Abraxas distinguishes single-ended from two-ended breaks unresolved"]},{"year":2019,"claim":"Clarified the dominant-negative disease mechanism, showing the heterozygous Finnish founder allele lowers BRCA1 levels and disrupts complex localization and the G2-M checkpoint.","evidence":"Patient-derived cells with Western blot, immunofluorescence, DNA repair pathway, and G2-M checkpoint assays","pmids":["31630195"],"confidence":"Medium","gaps":["Single lab; molecular basis of dominant-negative action on BRCA1 stability not fully defined","Did not map repair pathway redistribution"]},{"year":2023,"claim":"Connected genotype to repair pathway choice, showing C-terminal truncations redirect BRCA1 to the BRCA1-C complex and de-repress SSA and NHEJ in a dominant manner without impairing HR.","evidence":"Patient-derived lymphoblastoid and engineered mammary epithelial cells with HR reporter, RAD51 foci, SSA, NHEJ, and PARP inhibitor sensitivity assays","pmids":["37198153"],"confidence":"Medium","gaps":["Single lab; in vivo tumor relevance of the truncation alleles not tested","How retained N-terminal domains actively favor BRCA1-C assembly not mechanistically resolved"]},{"year":2022,"claim":"Reported a non-canonical interaction in which SUCNR1 binds ABRAXAS1 to activate PI3K/AKT signaling in gastric epithelial cells.","evidence":"Co-IP of SUCNR1–ABRAXAS1, SUCNR1 knockdown/inhibition, proliferation/invasion assays, and an in vivo gastric inflammation model","pmids":["41746808"],"confidence":"Low","gaps":["Single Co-IP interaction claim without reciprocal validation; ABRAXAS1 role in PI3K/AKT not independently confirmed","Relationship between this signaling role and the canonical BRCA1-A function unaddressed"]},{"year":null,"claim":"How the BRCA1-A complex and its deubiquitinase activity are spatiotemporally regulated to enforce repair pathway choice across break types, and whether the reported PI3K/AKT signaling role is genuine, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstitution defining how Abraxas tunes K63-ubiquitin turnover at damage sites","Independent confirmation of the SUCNR1–ABRAXAS1 signaling axis lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,7]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1,8,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7]}],"complexes":["BRCA1-A complex"],"partners":["BRCA1","RAP80","BRCC36"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UWZ7","full_name":"BRCA1-A complex subunit Abraxas 1","aliases":["Coiled-coil domain-containing protein 98","Protein FAM175A"],"length_aa":409,"mass_kda":46.7,"function":"Involved in DNA damage response and double-strand break (DSB) repair. Component of the BRCA1-A complex, acting as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6UWZ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABRAXAS1","classification":"Not Classified","n_dependent_lines":155,"n_total_lines":1208,"dependency_fraction":0.12831125827814568},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ABRAXAS1","total_profiled":1310},"omim":[{"mim_id":"611143","title":"ABRAXAS 1, BRCA1 A COMPLEX SUBUNIT; ABRAXAS1","url":"https://www.omim.org/entry/611143"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ABRAXAS1"},"hgnc":{"alias_symbol":["FLJ13614","ABRA1","ABRAXAS"],"prev_symbol":["CCDC98","FAM175A"]},"alphafold":{"accession":"Q6UWZ7","domains":[{"cath_id":"3.40.140.10","chopping":"4-170","consensus_level":"high","plddt":91.1839,"start":4,"end":170},{"cath_id":"-","chopping":"275-319","consensus_level":"medium","plddt":73.2182,"start":275,"end":319},{"cath_id":"1.20.5","chopping":"219-272","consensus_level":"medium","plddt":90.0311,"start":219,"end":272}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UWZ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UWZ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UWZ7-F1-predicted_aligned_error_v6.png","plddt_mean":77.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABRAXAS1","jax_strain_url":"https://www.jax.org/strain/search?query=ABRAXAS1"},"sequence":{"accession":"Q6UWZ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UWZ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UWZ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UWZ7"}},"corpus_meta":[{"pmid":"17525340","id":"PMC_17525340","title":"Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response.","date":"2007","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/17525340","citation_count":579,"is_preprint":false},{"pmid":"18077395","id":"PMC_18077395","title":"Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18077395","citation_count":357,"is_preprint":false},{"pmid":"17643122","id":"PMC_17643122","title":"CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response.","date":"2007","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17643122","citation_count":170,"is_preprint":false},{"pmid":"17643121","id":"PMC_17643121","title":"CCDC98 targets BRCA1 to DNA damage sites.","date":"2007","source":"Nature 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ABRAXAS1 mutation carrier cells.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31630195","citation_count":6,"is_preprint":false},{"pmid":"27270457","id":"PMC_27270457","title":"ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27270457","citation_count":6,"is_preprint":false},{"pmid":"37198153","id":"PMC_37198153","title":"ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways-lessons from breast cancer patients.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37198153","citation_count":4,"is_preprint":false},{"pmid":"24316840","id":"PMC_24316840","title":"Preliminary crystallographic studies of BRCA1 BRCT-ABRAXAS complex.","date":"2013","source":"Acta crystallographica. 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ABRAXAS1 gene mutations in the group of BRCA1-negative patients.","date":"2018","source":"Polish journal of pathology : official journal of the Polish Society of Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/30786683","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12391,"output_tokens":2957,"usd":0.040764,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10354,"output_tokens":3455,"usd":0.069072,"stage2_stop_reason":"end_turn"},"total_usd":0.109836,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Abraxas directly binds the BRCA1 BRCT repeats through a phospho-Ser-X-X-Phe (pSXXF) motif, forming a distinct BRCA1 complex (BRCA1-A complex) that is mutually exclusive with BACH1 and CtIP complexes. Abraxas recruits the UIM-containing protein RAP80 to BRCA1, and both are required for DNA damage resistance, G2-M checkpoint control, and DNA repair. RAP80's UIM domains were sufficient for foci formation, and RAP80-Abraxas together recruit BRCA1 to DNA damage sites partly through recognition of ubiquitinated proteins.\",\n      \"method\": \"Phosphopeptide affinity proteomics, Co-IP, siRNA knockdown with DNA damage resistance, G2-M checkpoint, and foci formation readouts\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (affinity proteomics, Co-IP, functional KD assays), replicated in same year by independent labs (PMIDs 17643122, 17643121)\",\n      \"pmids\": [\"17525340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Abraxas and BRCC36 associate through coiled-coil domains on each protein. RAP80 contains an Abraxas-interacting region (AIR) required for association of RAP80 with Abraxas, BRCA1, and BRCC36. The BRCA1-A complex is recruited to DNA damage foci via K63-linked polyubiquitin chains recognized by RAP80 UIM domains; this recruitment requires the E3 ubiquitin ligase RNF8 and the E2 enzyme Ubc13 to generate K63-polyubiquitin chains at damage sites.\",\n      \"method\": \"Co-IP, domain-deletion mapping, siRNA knockdown, foci formation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping with Co-IP and functional siRNA knockdown, multiple orthogonal experiments in one study, replicated contextually by PMID 17525340\",\n      \"pmids\": [\"18077395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CCDC98 (Abraxas) is a BRCA1-interacting protein that colocalizes with BRCA1 and is required for formation of BRCA1 foci in response to ionizing radiation, as well as for radiation sensitivity and damage-induced G2/M checkpoint control.\",\n      \"method\": \"Co-IP, immunofluorescence colocalization, siRNA knockdown with foci and checkpoint readouts\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent replication of PMID 17525340 findings with Co-IP and functional KD assays\",\n      \"pmids\": [\"17643122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CCDC98 (Abraxas) mediates BRCA1's association with RAP80 within the BRCA1-RAP80 complex and controls DNA damage-induced formation of BRCA1 foci and BRCA1-dependent G2/M checkpoint activation.\",\n      \"method\": \"Co-IP, siRNA knockdown with foci and checkpoint readouts\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent replication across multiple labs using Co-IP and functional assays\",\n      \"pmids\": [\"17643121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the BRCA1-BRCT/Abraxas complex revealed that ATM-dependent phosphorylation of Abraxas Ser404 (adjacent to the pSPxF motif) induces extensive interactions through the N-terminal sequence and leads to stable BRCT dimer formation at DNA damage sites. Mutation of S404 causes deficiency in BRCA1 accumulation at damage sites and cellular sensitivity to IR. Two germline BRCA1 mutations disrupt this dimer interface.\",\n      \"method\": \"X-ray crystallography, ATM-dependent phosphorylation assay, site-directed mutagenesis, IR sensitivity and foci formation assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional assays in a single rigorous study\",\n      \"pmids\": [\"26778126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A germline Abraxas mutation (c.1082G>A, Arg361Gln) abrogates nuclear localization of Abraxas and disrupts DNA damage response functions including BRCA1 foci formation and checkpoint control, identifying Abraxas as a breast cancer susceptibility gene.\",\n      \"method\": \"Patient mutation screening, nuclear localization assays, DNA damage response functional assays in carrier cells\",\n      \"journal\": \"Science Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cellular assays in patient-derived material, single lab\",\n      \"pmids\": [\"22357538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Abraxas exerts tumor suppressor function through binding to BRCA1 to regulate DNA repair and maintain genome stability; homozygous and heterozygous Abraxas knockout mice exhibited decreased survival and increased tumor incidence.\",\n      \"method\": \"Mouse knockout (homozygous and heterozygous), tumor incidence monitoring, DNA repair assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO mouse model with survival and tumor phenotype, DNA repair readouts, single lab\",\n      \"pmids\": [\"25066119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The Finnish ABRAXAS1 founder mutation (Arg361Gln), even in the heterozygous state, leads to decreased BRCA1 protein levels and reduced nuclear localization and foci formation of BRCA1 and CtIP, disturbs basal BRCA1-A complex localization, attenuates DNA damage response, and deregulates G2-M checkpoint control, acting in a dominant-negative manner on BRCA1.\",\n      \"method\": \"Patient-derived cells, Western blot, immunofluorescence, DNA repair pathway assays, G2-M checkpoint assays\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells with multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"31630195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Abraxas limits break-induced replication (BIR) at single-ended DSBs by counteracting K63-linked ubiquitin modification and thereby restricting SLX4/MUS81 recruitment to CPT-induced damage sites. Abraxas deficiency leads to uncontrolled SLX4/MUS81 loading, excessive MRE11/CtIP/DNA2-BLM-dependent end resection, and increased RAD52- and POLD3-dependent, RAD51-independent BIR and chromosome aberrations.\",\n      \"method\": \"Abraxas KO/KD with CPT treatment, mitotic DNA synthesis assays, ubiquitin modification assays, epistasis with SLX4/MUS81/RAD52/POLD3\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple pathway components, KO functional readouts, orthogonal assays in one study\",\n      \"pmids\": [\"34272385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Truncating germline mutations in ABRAXAS1 devoid of the C-terminal BRCA1 binding site, but retaining N-terminal interaction sites for RAP80, channel BRCA1 from the BRCA1-A complex to the BRCA1-C complex, inducing single-strand annealing (SSA). Further truncation deleting the coiled-coil region unleashes excessive DNA damage responses including SSA and NHEJ. ABRAXAS1 truncation thus de-represses multiple low-fidelity repair pathways in a dominant manner without impairing homologous recombination.\",\n      \"method\": \"Patient-derived lymphoblastoid cells, genetically manipulated mammary epithelial cells, HR reporter assay, RAD51 foci, SSA assay, NHEJ assay, PARP inhibitor sensitivity\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal repair pathway assays in patient cells plus engineered cells, single lab\",\n      \"pmids\": [\"37198153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUCNR1 (succinate receptor 1) directly interacts with ABRAXAS1 in gastric epithelial cells, and S. anginosus-derived succinate binding to SUCNR1 activates the PI3K/AKT signaling pathway through this interaction to promote gastric cancer progression.\",\n      \"method\": \"SUCNR1 knockdown, SUCNR1 inhibitor treatment, Co-IP (SUCNR1–ABRAXAS1 interaction), in vitro proliferation/invasion assays, in vivo gastric inflammation model\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP interaction claim, mechanistic follow-up limited, single lab, ABRAXAS1 role in PI3K/AKT not independently validated\",\n      \"pmids\": [\"41746808\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABRAXAS1 (Abraxas/CCDC98/FAM175A) is a scaffold protein that forms the BRCA1-A complex by directly binding the BRCA1 BRCT repeats via its C-terminal pSPxF phosphomotif (phosphorylation further stabilized by ATM-dependent S404 phosphorylation inducing BRCT dimerization), bridging RAP80 (through its N-terminal AIR region) and BRCC36 (through coiled-coil domains) to assemble the complex that is recruited to K63-ubiquitin chains at DNA damage sites generated by the RNF8–Ubc13 cascade; within this complex Abraxas restrains mutagenic break-induced replication by limiting SLX4/MUS81 loading and DNA end resection, maintains G2/M checkpoint fidelity, and channels BRCA1 into high-fidelity repair, while loss-of-function mutations de-repress low-fidelity pathways (SSA, BIR, NHEJ) and cause genomic instability and tumor predisposition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABRAXAS1 (Abraxas/CCDC98/FAM175A) is a scaffold protein that nucleates the BRCA1-A complex to channel BRCA1 into high-fidelity DNA double-strand break repair and enforce the G2/M checkpoint [#0, #2]. It binds the BRCA1 BRCT repeats directly through a C-terminal phospho-Ser-X-X-Phe (pSXXF) motif, forming a BRCA1 complex mutually exclusive with the BACH1 and CtIP complexes, while simultaneously recruiting the UIM-containing protein RAP80 to BRCA1 [#0]. Through coiled-coil contacts it also engages the deubiquitinase BRCC36, and RAP80's UIM domains recognize K63-linked polyubiquitin chains generated by the RNF8–Ubc13 cascade, recruiting the assembled complex to DNA damage foci [#1]. ATM-dependent phosphorylation of Ser404, adjacent to the pSPxF motif, drives stable BRCT dimer formation and is required for BRCA1 accumulation at damage sites and IR resistance [#4]. Beyond directing repair pathway choice, Abraxas restrains mutagenic break-induced replication by counteracting K63-ubiquitination and limiting SLX4/MUS81 loading and end resection at single-ended breaks, so that its loss de-represses low-fidelity pathways including BIR, single-strand annealing, and NHEJ [#8, #9]. Consistent with a genome-stabilizing tumor suppressor role, Abraxas knockout mice show increased tumor incidence [#6], and germline ABRAXAS1 mutations — including the Finnish founder Arg361Gln allele that abrogates nuclear localization and acts dominant-negatively on BRCA1 — confer breast cancer susceptibility [#5, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established Abraxas as a dedicated BRCA1 partner that defines a distinct BRCA1 complex and recruits RAP80, answering how BRCA1 is targeted to damage sites and partitioned among mutually exclusive complexes.\",\n      \"evidence\": \"Phosphopeptide affinity proteomics, Co-IP, and siRNA knockdown with DNA damage resistance, checkpoint, and foci readouts in human cells\",\n      \"pmids\": [\"17525340\", \"17643122\", \"17643121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the ubiquitin linkage type or upstream ligase generating the recruitment signal\", \"Structural basis of the pSXXF–BRCT interaction not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the molecular architecture of the complex and its recruitment route, showing Abraxas bridges BRCC36 via coiled-coils and RAP80 via the AIR, with foci formation depending on RNF8/Ubc13-generated K63-polyubiquitin.\",\n      \"evidence\": \"Co-IP, domain-deletion mapping, siRNA knockdown, and foci formation assays\",\n      \"pmids\": [\"18077395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the full complex not established\", \"Did not address how the complex influences downstream repair pathway choice\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked ABRAXAS1 to human disease by identifying a germline Arg361Gln mutation that abrogates nuclear localization and disrupts the DNA damage response, establishing it as a breast cancer susceptibility gene.\",\n      \"evidence\": \"Patient mutation screening with nuclear localization and DNA damage response functional assays in carrier cells\",\n      \"pmids\": [\"22357538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; penetrance and population frequency not addressed in this study\", \"Mechanism by which the mutation blocks nuclear import not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated in vivo tumor suppressor function, showing that Abraxas loss compromises genome stability and increases tumor incidence in mice.\",\n      \"evidence\": \"Homozygous and heterozygous knockout mice with survival monitoring, tumor incidence, and DNA repair assays\",\n      \"pmids\": [\"25066119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tumor spectrum and tissue specificity not fully resolved\", \"Did not dissect which downstream repair pathway defect drives tumorigenesis\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural mechanism of complex stabilization, showing ATM-dependent Ser404 phosphorylation drives BRCT dimerization required for BRCA1 retention at damage sites.\",\n      \"evidence\": \"X-ray crystallography of the BRCA1-BRCT/Abraxas complex with phosphorylation assays, mutagenesis, and IR sensitivity/foci readouts\",\n      \"pmids\": [\"26778126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics and reversibility of S404 phosphorylation in vivo not measured\", \"Functional consequence of dimerization for downstream repair not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed an active repair-restraining function, showing Abraxas limits break-induced replication by counteracting K63-ubiquitination and restricting SLX4/MUS81 recruitment and end resection.\",\n      \"evidence\": \"Abraxas KO/KD with CPT treatment, mitotic DNA synthesis and ubiquitin modification assays, and epistasis with SLX4/MUS81/RAD52/POLD3\",\n      \"pmids\": [\"34272385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The deubiquitinase activity responsible (e.g. BRCC36) not directly assigned in this restraint\", \"How Abraxas distinguishes single-ended from two-ended breaks unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Clarified the dominant-negative disease mechanism, showing the heterozygous Finnish founder allele lowers BRCA1 levels and disrupts complex localization and the G2-M checkpoint.\",\n      \"evidence\": \"Patient-derived cells with Western blot, immunofluorescence, DNA repair pathway, and G2-M checkpoint assays\",\n      \"pmids\": [\"31630195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; molecular basis of dominant-negative action on BRCA1 stability not fully defined\", \"Did not map repair pathway redistribution\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected genotype to repair pathway choice, showing C-terminal truncations redirect BRCA1 to the BRCA1-C complex and de-repress SSA and NHEJ in a dominant manner without impairing HR.\",\n      \"evidence\": \"Patient-derived lymphoblastoid and engineered mammary epithelial cells with HR reporter, RAD51 foci, SSA, NHEJ, and PARP inhibitor sensitivity assays\",\n      \"pmids\": [\"37198153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; in vivo tumor relevance of the truncation alleles not tested\", \"How retained N-terminal domains actively favor BRCA1-C assembly not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported a non-canonical interaction in which SUCNR1 binds ABRAXAS1 to activate PI3K/AKT signaling in gastric epithelial cells.\",\n      \"evidence\": \"Co-IP of SUCNR1–ABRAXAS1, SUCNR1 knockdown/inhibition, proliferation/invasion assays, and an in vivo gastric inflammation model\",\n      \"pmids\": [\"41746808\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP interaction claim without reciprocal validation; ABRAXAS1 role in PI3K/AKT not independently confirmed\", \"Relationship between this signaling role and the canonical BRCA1-A function unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the BRCA1-A complex and its deubiquitinase activity are spatiotemporally regulated to enforce repair pathway choice across break types, and whether the reported PI3K/AKT signaling role is genuine, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstitution defining how Abraxas tunes K63-ubiquitin turnover at damage sites\", \"Independent confirmation of the SUCNR1–ABRAXAS1 signaling axis lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"complexes\": [\"BRCA1-A complex\"],\n    \"partners\": [\"BRCA1\", \"RAP80\", \"BRCC36\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}