Affinage

ABRAXAS1

BRCA1-A complex subunit Abraxas 1 · UniProt Q6UWZ7

Length
409 aa
Mass
46.7 kDa
Annotated
2026-04-28
23 papers in source corpus 10 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ABRAXAS1 is a scaffold protein central to the BRCA1-A complex that orchestrates BRCA1 recruitment to DNA double-strand breaks and suppresses mutagenic repair pathways to maintain genome stability. It directly binds the BRCA1 BRCT repeats through a phospho-SPxF motif—further stabilized by ATM-dependent phosphorylation of S404, which induces BRCT/Abraxas dimerization required for efficient BRCA1 accumulation at damage sites—while simultaneously recruiting RAP80 (which recognizes RNF8/Ubc13-generated K63-polyubiquitin chains) and BRCC36 (via coiled-coil interactions) to assemble the damage-site signaling platform (PMID:17525340, PMID:18077395, PMID:26778126). Beyond recruiting BRCA1, ABRAXAS1 actively suppresses break-induced replication by counteracting K63-ubiquitin-dependent SLX4/MUS81 recruitment and restraining end resection, and its loss de-represses multiple low-fidelity DSB repair pathways including single-strand annealing and NHEJ (PMID:34272385, PMID:37198153). ABRAXAS1 functions as a tumor suppressor: knockout mice display increased tumor incidence and impaired DNA repair, and the Finnish founder mutation Arg361Gln acts in a dominant-negative manner to disrupt BRCA1 nuclear localization, DNA damage response, and G2/M checkpoint control, conferring cancer predisposition (PMID:25066119, PMID:22357538, PMID:31630195).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2007 High

    Identification of Abraxas as the direct BRCA1 BRCT-binding partner that nucleates a distinct BRCA1-A complex resolved the long-standing question of how BRCA1 is recruited to DNA damage sites independently of BACH1 and CtIP.

    Evidence Phosphopeptide affinity proteomics, reciprocal Co-IP, domain mapping, and siRNA knockdown with checkpoint/survival assays in human cells

    PMID:17525340 PMID:17643121 PMID:17643122

    Open questions at the time
    • Structural basis of the pSXXF–BRCT interaction not yet resolved
    • Stoichiometry and assembly order of the full BRCA1-A complex not determined
    • In vivo physiological significance not tested
  2. 2007 High

    Establishing the recruitment chain—RNF8/Ubc13-generated K63-polyubiquitin recognized by RAP80 UIMs, RAP80 bound to Abraxas, and BRCC36 associated via coiled-coil domains—defined the molecular logic by which the BRCA1-A complex localizes to damage-induced chromatin.

    Evidence Co-IP with domain deletion mutants, siRNA epistasis, and immunofluorescence foci assays

    PMID:18077395

    Open questions at the time
    • Mechanism by which BRCC36 deubiquitinase activity feeds back on K63-ubiquitin recognition was not addressed
    • Coiled-coil interaction between Abraxas and BRCC36 characterized only by deletion mutant Co-IP, no structural detail
  3. 2012 Medium

    Discovery that the patient-derived Arg361Gln mutation abolishes Abraxas nuclear localization and disrupts BRCA1-dependent checkpoint functions provided the first link between ABRAXAS1 dysfunction and human cancer predisposition.

    Evidence Patient-derived cells with immunofluorescence, checkpoint assays, and IR sensitivity

    PMID:22357538

    Open questions at the time
    • Single-lab study on one kindred; independent replication in additional families needed
    • Mechanism by which R361Q disrupts nuclear import not molecularly defined
  4. 2014 High

    Mouse knockout studies demonstrated that Abraxas is a bona fide tumor suppressor whose protective function depends on its BRCA1 BRCT interaction, establishing in vivo relevance beyond cell-based assays.

    Evidence Conditional knockout mouse model with tumor incidence monitoring and DNA repair assays

    PMID:25066119

    Open questions at the time
    • Tumor spectrum and tissue specificity of Abraxas loss not fully characterized
    • Whether haploinsufficiency alone drives tumorigenesis in mice was not fully resolved
  5. 2016 High

    Crystallographic resolution of the BRCT/Abraxas complex revealed that ATM-dependent phosphorylation of S404 induces dimerization of the BRCT/Abraxas unit, explaining how damage signaling amplifies BRCA1 accumulation at break sites.

    Evidence Crystal structure determination, S404A mutagenesis, IR-induced phosphorylation assay, foci and survival assays

    PMID:26778126

    Open questions at the time
    • Whether BRCT/Abraxas dimerization influences the stoichiometry or activity of other BRCA1-A subunits is unknown
    • Full-length complex structure not available
  6. 2019 Medium

    Characterization of heterozygous R361Q patient cells revealed a dominant-negative mechanism—reduced BRCA1 protein levels, impaired CtIP foci, and deregulated G2/M checkpoint—explaining how a monoallelic ABRAXAS1 mutation confers cancer risk.

    Evidence Patient-derived heterozygous lymphoblastoid cells with Western blot, immunofluorescence, checkpoint and DNA repair pathway assays

    PMID:31630195

    Open questions at the time
    • Single-lab study; mechanism of dominant-negative action (e.g., poisonous heterodimer) not structurally resolved
    • Penetrance and genotype–phenotype correlation in larger cohorts not established
  7. 2021 High

    Demonstration that Abraxas suppresses break-induced replication by restricting K63-ubiquitin-dependent SLX4/MUS81 recruitment and downstream end resection shifted understanding of Abraxas from a passive scaffold to an active suppressor of mutagenic repair.

    Evidence siRNA/CRISPR KO, proximity ligation assay, chromatin fractionation, mitotic DNA synthesis (EdU/FANCD2), chromosome aberration analysis

    PMID:34272385

    Open questions at the time
    • Whether Abraxas directly modulates K63-ubiquitin levels or acts indirectly through BRCC36 DUB activity is not fully delineated
    • Relative contribution of BIR suppression versus HR promotion to tumor suppression is unknown
  8. 2023 Medium

    Analysis of truncating ABRAXAS1 mutations showed that loss of the C-terminal BRCA1-binding site redirects BRCA1 to the BRCA1-C complex to activate SSA, while further loss of the coiled-coil region de-represses both SSA and NHEJ, revealing allele-specific pathway rewiring.

    Evidence Patient-derived lymphoblastoid cells, HR/SSA/NHEJ reporter assays, RAD51 foci, PARP-inhibitor sensitivity

    PMID:37198153

    Open questions at the time
    • Single-lab study; allele-specific repair pathway effects not validated in independent systems
    • How residual N-terminal Abraxas–RAP80 interaction channels BRCA1 to alternative complexes is mechanistically unclear
    • Clinical significance of SSA activation for therapeutic response is not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structure of the assembled BRCA1-A complex, the precise mechanism by which Abraxas coordinates BRCC36 DUB activity with BIR suppression, and the genotype–phenotype relationship for diverse ABRAXAS1 mutations in human cancer remain unresolved.
  • No full-length or cryo-EM structure of the complete BRCA1-A complex
  • Functional interdependence of Abraxas scaffold role and BRCC36 catalytic activity at damage sites not dissected
  • Systematic clinical studies correlating specific ABRAXAS1 mutations with repair pathway outcomes and cancer risk are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 2
Partners
BRCA1BRCC36CTIPMUS81RAP80RNF8SLX4
Complex memberships
BRCA1-A complex

Evidence

Reading pass · 12 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 excludes BACH1 and CtIP binding Phosphopeptide affinity proteomics, Co-IP, reciprocal pulldown Science High 17525340
2007 Abraxas recruits RAP80 to the BRCA1-A complex via a RAP80 Abraxas-interacting region (AIR domain), and RAP80 UIM domains recognize K63-linked polyubiquitin chains at DNA damage sites to recruit the entire BRCA1-A complex Co-IP, domain mapping, immunofluorescence (foci formation assay) Science High 17525340 18077395
2007 Abraxas and BRCC36 associate through coiled-coil domains on each protein as part of the BRCA1-A complex assembly Co-IP, domain mapping (coiled-coil deletion mutants) Proceedings of the National Academy of Sciences Medium 18077395
2007 RNF8 (E3 ubiquitin ligase) and Ubc13 (E2 conjugating enzyme) generate K63-linked polyubiquitin chains at DNA damage sites that are recognized by RAP80 UIM domains, enabling recruitment of Abraxas and the entire BRCA1-A complex to damage foci siRNA knockdown, Co-IP, immunofluorescence foci assay Proceedings of the National Academy of Sciences High 18077395
2007 Abraxas and RAP80 are required for DNA damage resistance, G2/M checkpoint control, and DNA repair (loss-of-function knockdown phenotype) siRNA knockdown, clonogenic survival, G2/M checkpoint assay Science High 17525340
2007 CCDC98 (Abraxas) mediates the interaction between BRCA1 and RAP80, and is required for BRCA1 foci formation and G2/M checkpoint activation in response to ionizing radiation Co-IP, siRNA knockdown, immunofluorescence foci assay, checkpoint assay Nature Structural & Molecular Biology High 17643121 17643122
2016 ATM-dependent phosphorylation of Abraxas serine 404 (adjacent to its pSPxF motif) induces dimerization of the BRCT/Abraxas complex, which is required for BRCA1 accumulation at DNA damage sites; crystal structure of BRCT/Abraxas complex revealed the molecular basis of this phosphorylation-dependent dimerization Crystal structure determination, mutagenesis (S404A), IR-induced phosphorylation assay, immunofluorescence foci assay, clonogenic survival Molecular Cell High 26778126
2012 The Abraxas Arg361Gln mutation abrogates nuclear localization of Abraxas and disrupts BRCA1-dependent DNA damage response functions (G2/M checkpoint, foci formation) Patient-derived cells, immunofluorescence, checkpoint assays, IR sensitivity Science Translational Medicine Medium 22357538
2014 Homozygous and heterozygous Abraxas knockout in mice leads to decreased survival, increased tumor incidence, and impaired DNA repair, demonstrating a tumor suppressor role that depends on BRCA1 BRCT domain interaction Conditional knockout mouse model, tumor incidence analysis, DNA repair assays Cell Reports High 25066119
2019 The Finnish ABRAXAS1 founder mutation (Arg361Gln), even in heterozygous state, causes decreased BRCA1 protein levels, reduced nuclear localization and foci formation of BRCA1 and CtIP, attenuated DNA damage response, and deregulated G2/M checkpoint in a dominant-negative manner Patient-derived heterozygous cells, Western blot, immunofluorescence, checkpoint assays, DNA repair pathway assays Human Molecular Genetics Medium 31630195
2021 Abraxas suppresses break-induced replication (BIR) by counteracting K63-linked ubiquitin modification to restrict SLX4/MUS81 recruitment to CPT-induced DNA damage sites, thereby limiting MRE11/CtIP/DNA2/BLM-mediated end resection and RAD52/POLD3-dependent, RAD51-independent mitotic DNA synthesis siRNA/CRISPR knockdown/KO, proximity ligation assay, chromatin fractionation, mitotic DNA synthesis assay (EdU/FANCD2 co-staining), chromosome aberration analysis Nature Communications High 34272385
2023 Truncating ABRAXAS1 mutations lacking the C-terminal BRCA1-binding site retain N-terminal interaction with RAP80, channeling BRCA1 from the BRCA1-A complex to the BRCA1-C complex and inducing single-strand annealing (SSA); further truncation deleting the coiled-coil region de-represses multiple low-fidelity DSB repair pathways including SSA and NHEJ Patient-derived lymphoblastoid cells, HR reporter assay, RAD51-foci, PARP-inhibitor sensitivity, SSA reporter assay, NHEJ assay, dominant-negative mutant expression Cell Death & Disease Medium 37198153

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.) 577 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 57 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 31 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) 19 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