Affinage

ABRAXAS1

BRCA1-A complex subunit Abraxas 1 · UniProt Q6UWZ7

Length
409 aa
Mass
46.7 kDa
Annotated
2026-06-09
23 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 High

    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

    PMID:17525340 PMID:17643121 PMID:17643122

    Open questions at the time
    • Did not resolve the ubiquitin linkage type or upstream ligase generating the recruitment signal
    • Structural basis of the pSXXF–BRCT interaction not defined
  2. 2007 High

    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

    PMID:18077395

    Open questions at the time
    • Stoichiometry and assembly order of the full complex not established
    • Did not address how the complex influences downstream repair pathway choice
  3. 2012 Medium

    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

    PMID:22357538

    Open questions at the time
    • Single lab; penetrance and population frequency not addressed in this study
    • Mechanism by which the mutation blocks nuclear import not defined
  4. 2014 High

    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

    PMID:25066119

    Open questions at the time
    • Tumor spectrum and tissue specificity not fully resolved
    • Did not dissect which downstream repair pathway defect drives tumorigenesis
  5. 2016 High

    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

    PMID:26778126

    Open questions at the time
    • Kinetics and reversibility of S404 phosphorylation in vivo not measured
    • Functional consequence of dimerization for downstream repair not directly tested
  6. 2021 High

    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

    PMID:34272385

    Open questions at the time
    • The deubiquitinase activity responsible (e.g. BRCC36) not directly assigned in this restraint
    • How Abraxas distinguishes single-ended from two-ended breaks unresolved
  7. 2019 Medium

    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

    PMID:31630195

    Open questions at the time
    • Single lab; molecular basis of dominant-negative action on BRCA1 stability not fully defined
    • Did not map repair pathway redistribution
  8. 2023 Medium

    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

    PMID:37198153

    Open questions at the time
    • 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
  9. 2022 Low

    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

    PMID:41746808

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No reconstitution defining how Abraxas tunes K63-ubiquitin turnover at damage sites
  • Independent confirmation of the SUCNR1–ABRAXAS1 signaling axis lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3
Partners
BRCA1BRCC36RAP80
Complex memberships
BRCA1-A complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. Phosphopeptide affinity proteomics, Co-IP, siRNA knockdown with DNA damage resistance, G2-M checkpoint, and foci formation readouts Science High 17525340
2007 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. Co-IP, domain-deletion mapping, siRNA knockdown, foci formation assays Proceedings of the National Academy of Sciences High 18077395
2007 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. Co-IP, immunofluorescence colocalization, siRNA knockdown with foci and checkpoint readouts Nature Structural & Molecular Biology High 17643122
2007 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. Co-IP, siRNA knockdown with foci and checkpoint readouts Nature Structural & Molecular Biology High 17643121
2016 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. X-ray crystallography, ATM-dependent phosphorylation assay, site-directed mutagenesis, IR sensitivity and foci formation assays Molecular Cell High 26778126
2012 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. Patient mutation screening, nuclear localization assays, DNA damage response functional assays in carrier cells Science Translational Medicine Medium 22357538
2014 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. Mouse knockout (homozygous and heterozygous), tumor incidence monitoring, DNA repair assays Cell Reports High 25066119
2019 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. Patient-derived cells, Western blot, immunofluorescence, DNA repair pathway assays, G2-M checkpoint assays Human Molecular Genetics Medium 31630195
2021 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. Abraxas KO/KD with CPT treatment, mitotic DNA synthesis assays, ubiquitin modification assays, epistasis with SLX4/MUS81/RAD52/POLD3 Nature Communications High 34272385
2023 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. Patient-derived lymphoblastoid cells, genetically manipulated mammary epithelial cells, HR reporter assay, RAD51 foci, SSA assay, NHEJ assay, PARP inhibitor sensitivity Cell Death & Disease Medium 37198153
2022 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. SUCNR1 knockdown, SUCNR1 inhibitor treatment, Co-IP (SUCNR1–ABRAXAS1 interaction), in vitro proliferation/invasion assays, in vivo gastric inflammation model Cell Reports Low 41746808

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science (New York, N.Y.) 579 17525340
2007 Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proceedings of the National Academy of Sciences of the United States of America 357 18077395
2007 CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. Nature structural & molecular biology 170 17643122
2007 CCDC98 targets BRCA1 to DNA damage sites. Nature structural & molecular biology 129 17643121
2016 Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites. Molecular cell 58 26778126
2012 Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions. Science translational medicine 46 22357538
2014 The BRCA1-interacting protein Abraxas is required for genomic stability and tumor suppression. Cell reports 32 25066119
2018 Sex Chromosomes of the Iconic Moth Abraxas grossulariata (Lepidoptera, Geometridae) and Its Congener A. sylvata. Genes 24 29857494
2011 Tubulin, BRCA1, ERCC1, Abraxas, RAP80 mRNA expression, p53/p21 immunohistochemistry and clinical outcome in patients with advanced non small-cell lung cancer receiving first-line platinum-gemcitabine chemotherapy. Lung cancer (Amsterdam, Netherlands) 20 21529986
2021 Abraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage. Nature communications 16 34272385
2008 Analysis of the genes coding for the BRCA1-interacting proteins, RAP80 and Abraxas (CCDC98), in high-risk, non-BRCA1/2, multiethnic breast cancer cases. Breast cancer research and treatment 15 18695986
2014 Regulation of the AbrA1/A2 two-component system in Streptomyces coelicolor and the potential of its deletion strain as a heterologous host for antibiotic production. PloS one 13 25303210
2017 Mitochondrial genome of Abraxas suspecta (Lepidoptera: Geometridae) and comparative analysis with other Lepidopterans. Zootaxa 12 28609941
2018 Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts. Cell death & disease 11 29497033
2020 Kaposi Sarcoma in Association With an Extracavitary Primary Effusion Lymphoma Showing Unusual Intravascular Involvement: Report of a Case Harboring a FAM175A Germline Mutation. The American Journal of dermatopathology 9 31361614
2019 BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous ABRAXAS1 mutation carrier cells. Human molecular genetics 6 31630195
2016 ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry. PloS one 6 27270457
2023 ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways-lessons from breast cancer patients. Cell death & disease 4 37198153
2013 Preliminary crystallographic studies of BRCA1 BRCT-ABRAXAS complex. Acta crystallographica. Section F, Structural biology and crystallization communications 3 24316840
2014 Mislocalization of BRCA1-complex due to ABRAXAS Arg361Gln mutation. Journal of biomolecular structure & dynamics 1 25105795
2026 Streptococcus anginosus-generated succinate promotes the progression of gastric cancer via the succinate/SUCNR1/ABRAXAS1 axis. Cell reports 0 41746808
2020 Transcriptional regulation of human abraxas brother protein 1 expression by yin yang 1. Biochemistry and cell biology = Biochimie et biologie cellulaire 0 32845162
2018 Searching for new breast cancer-associated genes. ABRAXAS1 gene mutations in the group of BRCA1-negative patients. Polish journal of pathology : official journal of the Polish Society of Pathologists 0 30786683

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