Affinage

BRCA1

Breast cancer type 1 susceptibility protein · UniProt P38398

Round 2 corrected
Length
1863 aa
Mass
207.7 kDa
Annotated
2026-04-28
130 papers in source corpus 37 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRCA1 is a nuclear tumor suppressor that functions as a RING-type E3 ubiquitin ligase and central coordinator of the DNA damage response, homologous recombination repair, replication fork protection, and transcriptional regulation. BRCA1 heterodimerizes with BARD1 through its RING domain to ubiquitinate nucleosomal H2A, with substrate specificity determined by BARD1 recognition of DSB-specific monoubiquitin marks on H2A K13/K15 (PMID:34321665); it is phosphorylated by ATM and ATR kinases at SQ/TQ clusters following DNA damage, which is required for radiation resistance (PMID:10550055, PMID:11114888). BRCA1 promotes homologous recombination by interacting with RAD51, antagonizing 53BP1/RIF1-mediated end-protection to favor DNA end resection in S/G2 phase, and protecting stalled replication forks from degradation in an epistatic pathway with FANCD2 and RAD51 (PMID:9008167, PMID:10549283, PMID:20453858, PMID:22789542). Germline loss-of-function mutations in BRCA1 cause hereditary breast and ovarian cancer susceptibility (PMID:7545954).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1990 High

    Before the gene was cloned, linkage analysis established that a breast cancer susceptibility locus resided on chromosome 17q21, defining the target for positional cloning.

    Evidence Genetic linkage (LOD score) with RFLP markers in early-onset breast cancer families

    PMID:2270482

    Open questions at the time
    • Gene identity unknown
    • No protein or functional information
  2. 1994 High

    Positional cloning identified BRCA1 as an 1863-amino-acid protein harboring a zinc-finger domain, with frameshift, nonsense, and missense mutations segregating in familial breast/ovarian cancer kindreds, establishing it as a tumor suppressor gene.

    Evidence Positional cloning with mutation sequencing and linkage analysis in affected families

    PMID:7545954

    Open questions at the time
    • Biochemical activity unknown
    • Cellular function uncharacterized
    • No structural data
  3. 1997 High

    Demonstration that BRCA1 colocalizes and physically interacts with RAD51 in S-phase nuclear foci and on meiotic chromosomes, and that DNA damage triggers BRCA1 hyperphosphorylation and redistribution to PCNA-positive replication structures, established BRCA1 as a participant in DNA repair and replication checkpoint responses.

    Evidence Co-immunoprecipitation, in vitro binding, immunofluorescence, phosphorylation shift assays in mitotic and meiotic cells

    PMID:9008167 PMID:9267023

    Open questions at the time
    • Enzymatic activity of BRCA1 unknown
    • Upstream kinase not identified
    • Mechanism of RAD51 cooperation unclear
  4. 1998 High

    BRCA1 was shown to bind p53 and co-activate p53-dependent transcription from p21 and bax promoters, with cancer-derived mutants defective in this activity, revealing a transcriptional co-activator function linked to tumor suppression.

    Evidence Co-IP, GST pulldown, transcriptional reporter assays, domain mapping

    PMID:9582019

    Open questions at the time
    • Direct versus indirect transcriptional mechanism unclear
    • Genome-wide transcriptional targets unknown
  5. 1999 High

    Three key mechanistic advances established BRCA1's enzymatic identity and upstream regulation: the RING finger was shown to confer E2-dependent E3 ubiquitin ligase activity; ATM was identified as the kinase that phosphorylates BRCA1 at SQ clusters after ionizing radiation (required for radiation resistance); and Brca1-null ES cells were proven defective in homologous recombination repair of DSBs.

    Evidence In vitro ubiquitination with RING mutagenesis; in vitro kinase assay with ATM plus complementation rescue; DSB repair frequency assay in Brca1-knockout ES cells

    PMID:10500182 PMID:10549283 PMID:10550055

    Open questions at the time
    • Physiological ubiquitin substrates unidentified
    • How E3 activity relates to HR unclear
    • BARD1 contribution to E3 activity not yet dissected
  6. 2000 High

    BRCA1 was found to organize a large nuclear surveillance complex (BASC) containing mismatch repair, BLM helicase, MRN complex, ATM, and RFC, and ATR was identified as a second damage-responsive kinase directly phosphorylating BRCA1 at Ser1423, positioning BRCA1 as a central scaffold integrating multiple repair and checkpoint pathways.

    Evidence IP-mass spectrometry, co-IP, colocalization; in vitro kinase assay with dominant-negative ATR and phospho-specific antibodies

    PMID:10783165 PMID:11114888

    Open questions at the time
    • Stoichiometry and dynamics of BASC unknown
    • Which ATR phosphosites are functionally essential beyond Ser1423 unclear
  7. 2001 High

    Monoubiquitinated FANCD2 was shown to colocalize with BRCA1 at damage-induced foci, linking the Fanconi anemia pathway to BRCA1-dependent DNA repair and establishing a functional convergence of these tumor suppressor networks.

    Evidence Co-IP, immunofluorescence colocalization, monoubiquitination shift assay

    PMID:11239454

    Open questions at the time
    • Direct physical interaction between BRCA1 and FANCD2 not demonstrated at that time
    • Mechanistic basis of functional epistasis unclear
  8. 2002 High

    BRCA1 was found to colocalize with the inactive X chromosome, associate with XIST RNA, and be required for maintenance of XIST RNA concentration and X-linked gene silencing, revealing an unexpected role in epigenetic chromosome regulation beyond DNA repair.

    Evidence ChIP for XIST RNA association, immunofluorescence, reconstitution in BRCA1-deficient cells, GFP reporter assay

    PMID:12419249

    Open questions at the time
    • Whether XIST association is direct RNA binding or indirect via chromatin
    • Relevance to tumor suppression not established
  9. 2004 High

    Multiple studies expanded BRCA1's functional repertoire: BRCA1 ubiquitinates topoisomerase IIα to stimulate decatenation activity and ensure chromosome segregation; RING and BRCT domains cooperate for damage-induced foci recruitment; and CRM1-dependent nuclear export of BRCA1 after irradiation requires p53.

    Evidence Co-IP/ubiquitination/decatenation assays; YFP domain mapping in irradiated cells; subcellular fractionation with CRM1 inhibitor and p53 perturbation

    PMID:15087457 PMID:15569676 PMID:15965487

    Open questions at the time
    • In vivo relevance of topoisomerase IIα ubiquitination for tumor suppression
    • Structural basis of RING-BRCT cooperation unknown
  10. 2007 High

    The upstream chromatin signaling cascade recruiting BRCA1 to DSBs was defined: RNF8 ubiquitylates H2A/H2AX at breaks via MDC1, and the adaptor Abraxas/CCDC98 bridges RAP80 to BRCA1 for focal accumulation and G2/M checkpoint activation, establishing the BRCA1-A complex architecture.

    Evidence Co-IP, in vitro ubiquitination, siRNA knockdown, checkpoint assays, X-ray crystallography of RNF8 FHA domain

    PMID:17643121 PMID:18001824

    Open questions at the time
    • How BRCA1-A complex is disassembled after repair
    • Relative contributions of multiple BRCA1 subcomplexes (A, B, C) to repair not resolved
  11. 2009 High

    BAP1 deubiquitinase was shown to bind the BARD1 RING domain via SPR, competing with BRCA1 heterodimerization and inhibiting BRCA1/BARD1 autoubiquitination through both enzymatic and steric mechanisms; separately, BRCA1 E3 ligase activity was shown to mono-ubiquitinate ERα, blocking p300-mediated acetylation and repressing ERα transcriptional activity.

    Evidence Surface plasmon resonance, in vitro ubiquitination/acetylation assays, catalytic mutant analysis, shRNA knockdown

    PMID:19117993 PMID:19887647

    Open questions at the time
    • Physiological regulation of BAP1–BARD1 competition in vivo
    • Whether ERα ubiquitination occurs genome-wide or at specific loci
  12. 2010 Medium

    BRCA1 was shown to regulate its own promoter through an E2F1/RB-containing repressive complex (disrupted by genotoxic stress) and to maintain DNMT1 expression and genomic DNA methylation, extending its transcriptional regulatory roles to epigenomic maintenance and autoregulation.

    Evidence Tandem ChIP (Re-ChIP), promoter reporter assays, bisulfite sequencing in Brca1-mutant mouse models

    PMID:20068145 PMID:20820192

    Open questions at the time
    • In vivo significance of autoregulatory loop for tumor suppression unclear
    • DNMT1 regulation not validated beyond one lab
  13. 2012 High

    Two genetic epistasis studies resolved how BRCA1 governs DSB repair pathway choice and fork protection: loss of 53BP1 rescued HR and checkpoint defects of Brca1-deleted cells (but not Brca2-deleted), defining BRCA1 as antagonizing 53BP1-mediated end protection; separately, BRCA1 and FANCD2 were shown to protect stalled replication forks from degradation in an epistatic pathway with RAD51.

    Evidence Conditional knockout epistasis in mouse cells with HR/checkpoint/drug sensitivity assays; DNA fiber assay with siRNA knockdown and RAD51 rescue

    PMID:20453858 PMID:22789542

    Open questions at the time
    • Molecular mechanism by which BRCA1 displaces 53BP1 not known at this time
    • Whether fork protection and HR functions are separable
  14. 2013 High

    RIF1 was identified as the 53BP1 effector antagonized by BRCA1: RIF1 blocks end resection in G1, and BRCA1 counteracts RIF1 accumulation at DSBs in S/G2, providing a cell-cycle-dependent mechanism for repair pathway choice between NHEJ and HR.

    Evidence siRNA epistasis, immunofluorescence foci, end resection assay, cell cycle fractionation

    PMID:23486525

    Open questions at the time
    • Direct biochemical mechanism of RIF1 displacement by BRCA1 not resolved
    • How BRCA1 senses cell cycle phase at individual DSBs unclear
  15. 2014 High

    Neural progenitor-specific Brca1 deletion caused severe brain agenesis through p53-dependent apoptosis, while centrosomal/polarity defects were ATM-dependent but p53-independent, establishing that BRCA1 has genetically separable apoptotic and centrosomal functions in vivo.

    Evidence Conditional KO mouse genetics with p53 and ATM double-KO epistasis, histology, immunofluorescence

    PMID:24639535

    Open questions at the time
    • Centrosomal substrate of BRCA1 E3 ligase in neural progenitors unidentified
    • Whether neural phenotype contributes to cancer predisposition unknown
  16. 2021 High

    Cryo-EM structure of BRCA1-BARD1 on a nucleosome revealed how BARD1 recognizes DSB-specific H2A K13/K15 monoubiquitin marks and positions the RING-E2 module to ubiquitinate H2A/H2AX C-terminal tails, explaining chromatin recruitment specificity and substrate selectivity of the heterodimer; concurrently, SIRT2 was shown to deacetylate BARD1 RING lysines to promote BRCA1-BARD1 heterodimerization, stability, and nuclear retention.

    Evidence Cryo-EM structure determination with biochemical ubiquitination and mutagenesis; Co-IP, in vitro deacetylation, HR assay, nuclear fractionation

    PMID:33789098 PMID:34321665

    Open questions at the time
    • Full-length BRCA1-BARD1 structure not yet resolved
    • In vivo dynamics of SIRT2-mediated BARD1 deacetylation during the cell cycle unknown
  17. 2024 Medium

    BRCA1 was found to transcriptionally regulate VDAC3 and GPX4, positioning it as a dual regulator of ferroptosis: BRCA1 deficiency blocks VDAC3-dependent ferroptosis while sensitizing cells to GPX4 inhibitor-induced ferroptosis, synergizing with PARP inhibition in BRCA1-deficient cancers.

    Evidence CRISPR/siRNA knockdown, ChIP, ferroptosis assays, xenograft and patient-derived xenograft models

    PMID:38552003

    Open questions at the time
    • Whether ferroptosis regulation is a primary tumor-suppressive function or secondary consequence of transcriptional dysregulation
    • VDAC3/GPX4 regulation not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full spectrum of physiological BRCA1-BARD1 ubiquitin substrates beyond H2A, the structural basis by which BRCA1 displaces 53BP1/RIF1 at DSBs during S/G2, whether BRCA1's diverse non-repair functions (X-inactivation, ferroptosis regulation, centrosome control) contribute independently to tumor suppression, and how BRCA1 coordinates its scaffolding, enzymatic, and transcriptional activities at a single damage site.
  • Comprehensive substrate identification for BRCA1-BARD1 E3 ligase lacking
  • Structural mechanism of 53BP1/RIF1 antagonism unresolved
  • Contribution of individual BRCA1 functions to tissue-specific tumorigenesis unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 7 GO:0005694 chromosome 4
Pathway
R-HSA-73894 DNA Repair 11 R-HSA-1640170 Cell Cycle 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-8953897 Cellular responses to stimuli 6 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-69306 DNA Replication 3 R-HSA-1643685 Disease 2 R-HSA-8953854 Metabolism of RNA 1
Partners
ABRAXAS1BAP1BARD1FANCD2RAD51RAP80RIF1TP53
Complex memberships
BASC (BRCA1-associated genome surveillance complex)BRCA1-A complex (RAP80/Abraxas/MERIT40/BRCC36/BRE)BRCA1-BARD1 heterodimer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 BRCA1 was positionally cloned on chromosome 17q21, encoding a predicted 1863-amino-acid protein with a zinc finger domain in its amino-terminal region; probable predisposing mutations (frameshift, nonsense, missense, regulatory) were identified in familial breast/ovarian cancer kindreds. Positional cloning, mutation sequencing, linkage analysis Science High 7545954
1990 A susceptibility locus for early-onset familial breast cancer was mapped to chromosome 17q21 by linkage analysis, establishing the chromosomal location of BRCA1. Genetic linkage analysis (LOD score analysis of RFLP markers) Science High 2270482
1997 BRCA1 colocalizes with RAD51 in discrete nuclear foci during S phase of the cell cycle, co-immunoprecipitates with RAD51, and BRCA1 residues 758–1064 alone form RAD51-containing complexes in vitro; both proteins associate with synaptonemal complexes in meiotic cells, suggesting a functional interaction in recombination and genome integrity control. Co-immunoprecipitation, in vitro binding assay, immunofluorescence colocalization, meiotic chromosome spreads Cell High 9008167
1997 BRCA1 localizes to discrete S-phase nuclear foci that disperse upon DNA damage (UV, gamma-irradiation, mitomycin C, hydroxyurea); dispersal is accompanied by DNA damage-induced hyperphosphorylation of BRCA1 and redistribution of BRCA1/BARD1/RAD51 complexes to PCNA-positive replication structures, implicating BRCA1-containing complexes in a replication checkpoint response. Immunofluorescence, cell fractionation, Western blot phosphorylation shift analysis, co-immunoprecipitation Cell High 9267023
1999 ATM kinase is required for BRCA1 phosphorylation in response to ionizing radiation; ATM resides in a complex with BRCA1 and phosphorylates BRCA1 in vivo and in vitro at serine-glutamine clusters; a BRCA1 mutant lacking two ATM phosphorylation sites fails to rescue radiation hypersensitivity of BRCA1-deficient cells. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, complementation of radiation hypersensitivity Science High 10550055
1999 BRCA1 RING finger domain mediates E2-dependent ubiquitination; mutations of metal-coordinating residues in the RING finger abolish ubiquitination activity, establishing BRCA1 as a RING-type E3 ubiquitin ligase. In vitro ubiquitination assay, mutagenesis of RING finger zinc-coordinating residues, chelation of zinc Proceedings of the National Academy of Sciences High 10500182
1999 Brca1-deficient mouse embryonic stem cells have impaired repair of chromosomal double-strand breaks by homologous recombination, with altered frequencies of homologous versus nonhomologous DNA integration, demonstrating a caretaker role for BRCA1 in promoting homologous recombination. Gene targeting, DSB repair frequency assay in ES cells, Southern blotting Molecular Cell High 10549283
2000 BRCA1 associates with a large nuclear surveillance complex (BASC) containing MSH2, MSH6, MLH1, ATM, BLM, RAD50-MRE11-NBS1, and RFC; BRCA1, BLM, and RAD50-MRE11-NBS1 colocalize to nuclear foci containing PCNA after agents that block DNA synthesis, placing BRCA1 as a coordinator of multiple DNA repair and replication activities. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, immunofluorescence colocalization Genes & Development High 10783165
2000 ATR kinase phosphorylates BRCA1 on six Ser/Thr residues including Ser1423 in vitro; kinase-inactive ATR suppresses Ser1423 phosphorylation after HU or UV treatment; ATR forms nuclear foci overlapping BRCA1 foci at stalled replication forks, demonstrating ATR directly phosphorylates BRCA1 in response to DNA damage or replication stress. In vitro kinase assay, dominant-negative ATR expression, immunofluorescence colocalization, phospho-specific antibodies Genes & Development High 11114888
2001 FANCD2, activated by monoubiquitination through a nuclear FA complex (FANCA/FANCC/FANCF/FANCG), colocalizes with BRCA1 in ionizing radiation-induced nuclear foci and on synaptonemal complexes, linking the Fanconi anemia pathway to the BRCA1 DNA repair machinery. Co-immunoprecipitation, immunofluorescence colocalization, Western blot (monoubiquitination shift), cell fractionation Molecular Cell High 11239454
1998 BRCA1 physically associates with p53 in vitro and in vivo, mapping to BRCA1 aa 224–500 and the p53 C-terminal domain; BRCA1 stimulates p53-dependent transcription from p21WAF1/CIP1 and bax promoters; tumor-derived BRCA1 mutants are defective in p53 co-activation; BRCA1 and p53 cooperatively induce apoptosis. Co-immunoprecipitation, GST pulldown, transient transfection transcriptional reporter assay, apoptosis assay, domain mapping Oncogene High 9582019
2002 BRCA1 colocalizes with markers of the inactive X chromosome and associates with XIST RNA (detected by ChIP); reconstitution of BRCA1-deficient cells with wild-type BRCA1 restores focal XIST RNA staining; inhibiting BRCA1 synthesis in a reporter line leads to increased expression of a silenced Xi-located GFP transgene, demonstrating BRCA1 supports XIST RNA concentration and inactive X chromosome maintenance. Immunofluorescence colocalization, chromatin immunoprecipitation, reconstitution assay, GFP reporter gene expression assay Cell High 12419249
2004 C. elegans BRC-1 (BRCA1 ortholog) and BRD-1 (BARD1 ortholog) are required for DNA repair; their depletion causes elevated p53-dependent germ cell death, impaired progeny survival after irradiation, and chromosome fragmentation, functionally conserving the BRCA1/BARD1 repair pathway. RNAi depletion, irradiation survival assay, genetic epistasis, cytological analysis Current Biology High 14711411
2005 BRCA1 interacts and colocalizes with topoisomerase IIα in S-phase cells; BRCA1-deficient cells show lagging chromosomes and defective DNA decatenation in vitro; topoisomerase IIα is ubiquitinated in a BRCA1-dependent manner, and this ubiquitination correlates with higher decatenation activity, revealing a BRCA1 role in DNA decatenation and chromosome segregation. Co-immunoprecipitation, immunofluorescence, in vitro decatenation assay, chromosome analysis, ubiquitination assay Nature Structural & Molecular Biology High 15965487
2007 CCDC98 (Abraxas) mediates BRCA1 association with RAP80 and is required for DNA damage-induced BRCA1 nuclear foci formation and BRCA1-dependent G2/M checkpoint activation. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, checkpoint assay Nature Structural & Molecular Biology High 17643121
2007 RNF8 ubiquitylates histone H2A and H2AX at DNA double-strand breaks via its RING domain after phospho-dependent binding to MDC1 through its FHA domain; this ubiquitylation is required for accumulation of BRCA1 (and 53BP1) at DSB sites; RNF8 depletion impairs G2/M checkpoint and increases IR sensitivity. Co-immunoprecipitation, in vitro ubiquitination, siRNA knockdown, immunofluorescence, checkpoint assay, X-ray crystallography of FHA domain Cell High 18001824 18001825
2008 BRCA1 binds the SIRT1 promoter and increases SIRT1 expression; SIRT1 in turn inhibits Survivin by altering histone H3 epigenetic modifications; absence of SIRT1 blocks BRCA1-mediated Survivin regulation; demonstrated in Brca1-mutant mouse mammary tumors and in vitro. Chromatin immunoprecipitation, promoter reporter assay, siRNA knockdown, Western blot, mouse tumor model Molecular Cell Medium 18851829
2009 BAP1 (ubiquitin C-terminal hydrolase) interacts with the BARD1 RING domain (residues 182–365 of BAP1) via surface plasmon resonance; BAP1 interferes with BRCA1/BARD1 heterodimerization, inhibiting BRCA1/BARD1 autoubiquitination and NPM1/B23 ubiquitination; a catalytically inactive BAP1 mutant (C91S) also inhibits ubiquitination, indicating a second steric mechanism; BAP1 depletion causes IR hypersensitivity and S-phase retardation. Surface plasmon resonance (BIAcore), in vitro ubiquitination assay, catalytic mutant analysis, shRNA knockdown, cell cycle assay Cancer Research High 19117993
2009 BRCA1 overexpression reduces acetylated ER-α levels and increases mono-ubiquitinated ER-α; a BRCA1 ubiquitin ligase-dead mutant (I26A) neither ubiquitinates ER-α nor represses its activity; in vitro, BRCA1 inhibits p300-mediated acetylation of ER-α; a cancer-associated BRCA1 mutant (C61G) lacks this activity, linking BRCA1 E3 ligase activity to regulation of ER-α via competing acetylation/ubiquitination. In vitro ubiquitination assay, in vitro acetylation assay, siRNA knockdown, Western blot, transient transfection reporter assay Molecular Endocrinology High 19887647
2009 MERIT40 is a component of the RAP80/CCDC98-containing BRCA1-A complex; it interacts directly with BRE/BRCC45 to maintain complex stability; MERIT40 is required for BRCA1 retention at DNA breaks and for checkpoint function. Co-immunoprecipitation, siRNA knockdown, immunofluorescence foci assay, checkpoint assay, protein stability assay Genes & Development High 19261748
2010 BRCA1 deficiency leads to global DNA hypomethylation and loss of genomic imprinting; BRCA1 binds the DNMT1 promoter through a potential OCT1 site and maintains transcriptional activity of DNMT1; demonstrated in BRCA1-mutant mouse models and human clinical samples. Chromatin immunoprecipitation, promoter assay, bisulfite sequencing, mouse knockout model, Western blot Cell Research Medium 20820192
2010 BRCA1 assembles with E2F-1 and RB to form a repressive transcriptional complex at the BRCA1 promoter; genotoxic stress disrupts this complex, displacing BRCA1 and upregulating BRCA1 transcription, defining an autoregulatory loop; demonstrated by tandem ChIP. Tandem chromatin immunoprecipitation (Re-ChIP), siRNA knockdown, promoter reporter assay, Western blot Cancer Research Medium 20068145
2010 BRCA1 expression is controlled by a CtBP-containing co-repressor complex regulating HDAC1 and histone acetylation at the BRCA1 promoter; eviction of CtBP by estrogen, siRNA, or elevated NAD+/NADH leads to HDAC1 dismissal and increased BRCA1 transcription, revealing a metabolic switch coupling caloric intake to tumor suppressor expression. Chromatin immunoprecipitation, siRNA knockdown, NAD+/NADH metabolic manipulation, HDAC inhibitor treatment, promoter reporter assay Nature Structural & Molecular Biology Medium 21102443
2012 Loss of 53BP1 rescues the growth arrest, checkpoint defects, and partially rescues the homologous recombination defect and DNA damage hypersensitivity of Brca1-deleted cells; 53BP1 acts downstream of ATM to sustain the checkpoint response in BRCA1-deficient cells; this rescue is specific to BRCA1 (not BRCA2) deficiency, defining an epistatic relationship between BRCA1 and the 53BP1 pathway in DNA repair pathway choice. Conditional knockout mouse cells, siRNA knockdown, HR assay, checkpoint assay, drug hypersensitivity assay Nature Structural & Molecular Biology High 20453858
2012 FANCD2 and BRCA1 are required for protection of stalled replication forks from degradation in a repair-independent manner; this fork protection is epistatic with RAD51 stabilization, linking FA genes, RAD51, and BRCA1/2 in a unified fork protection pathway. DNA fiber assay (replication fork degradation), siRNA knockdown, RAD51 overexpression rescue, genetic epistasis Cancer Cell High 22789542
2013 RIF1 translocates to DNA damage sites via ATM-dependent 53BP1 phosphorylation and counteracts BRCA1-mediated DNA end resection; loss of RIF1 rescues end resection and checkpoint activation in BRCA1-depleted cells; BRCA1 antagonizes RIF1 accumulation at damage sites in S/G2, while RIF1 inhibits BRCA1 recruitment in G1; RIF1 also promotes BLM chromatin loading independently of 53BP1. siRNA knockdown, immunofluorescence foci assay, end resection assay, checkpoint assay, cell cycle fractionation Journal of Biological Chemistry High 23486525
2004 Casein kinase 2 beta-subunit binds BRCA1 C-terminal region (identified by yeast two-hybrid and confirmed in Sf9 cells); CK2 phosphorylates BRCA1 in vitro, requiring Ser1572; the cancer-associated missense mutant M1775R shows weaker CK2 association. Yeast two-hybrid, in vitro kinase assay, site-directed mutagenesis, Sf9 cell expression Biochemical and Biophysical Research Communications Medium 10403822
2004 The BRCA1 RING and BRCT domains cooperate to target BRCA1 to ionizing radiation-induced nuclear foci; cancer-specific mutations in the BRCT domain abolish foci recruitment; neither domain alone is sufficient, but their combination restores foci targeting, co-localizing with MDC1. YFP-BRCA1 domain mapping in MCF-7 cells, immunofluorescence after ionizing radiation, dominant-negative competition Journal of Biological Chemistry Medium 15569676
2004 BRCA1-IRIS, a distinct BRCA1 locus product encoded from codon 1 through intron 11, is exclusively chromatin-associated, does not interact with BARD1 in vivo or in vitro, co-immunoprecipitates with DNA replication-licensing proteins, and suppression of BRCA1-IRIS impairs DNA replication initiation while overexpression stimulates it. [Note: classified as a distinct protein isoform/alt product from the BRCA1 locus; KEEP as it describes a direct protein product and its mechanistic distinction from p220 BRCA1 is itself a mechanistic finding about the locus.] Co-immunoprecipitation, immunostaining, BRCA1-IRIS siRNA knockdown, DNA replication assay, chromatin fractionation Nature Cell Biology Medium 15448696
2003 BRCA1 associates specifically with hyperphosphorylated, elongating RNA polymerase II (pol IIO) rather than the hypophosphorylated initiating form (pol IIA); BRCA1-RNA pol II complexes are functional in transcriptional run-off assays; interaction is disrupted by DNA-damaging agents, placing BRCA1 in position to link processive transcription with DNA repair surveillance. Subcellular fractionation, co-immunoprecipitation, in vitro transcriptional run-off assay, phospho-specific antibodies Journal of Biological Chemistry Medium 14506230
2004 Ionizing radiation stimulates BRCA1 nuclear export in a dose-dependent and CRM1-dependent manner; this export requires wild-type p53 function (abrogated by HPV E6); BRCA1 localization varies across the cell cycle and is regulated by p53-dependent mechanisms in addition to kinase-dependent phosphorylation. Immunohistochemical staining, subcellular fractionation and Western blot, CRM1 inhibitor (leptomycin B), inducible p53 system, cell cycle fractionation Journal of Biological Chemistry Medium 15087457
2021 Cryo-EM structure of BRCA1-BARD1 on a nucleosome reveals that BARD1 ankyrin repeat and tandem BRCT domains adopt a compact fold binding nucleosomal histones, DNA, and monoubiquitin on H2A K13/K15 (DSB-specific marks); RING domains orient an E2 enzyme atop the nucleosome for ubiquitin transfer to H2A/H2AX C-terminal tails; recognition of N-terminal H2A monoubiquitin blocks polyubiquitin chain formation and cooperatively promotes C-terminal H2A ubiquitylation, explaining BRCA1-BARD1 chromatin recruitment and specificity. Cryo-electron microscopy structure determination, biochemical ubiquitination assay, mutagenesis Nature High 34321665
2021 SIRT2 deacetylase complexes with BRCA1-BARD1 and deacetylates conserved lysines in the BARD1 RING domain at the BRCA1-BARD1 interface, promoting heterodimerization, mutual stability, nuclear retention, and localization to DNA damage sites, thereby facilitating homologous recombination. Co-immunoprecipitation, in vitro deacetylation assay, siRNA knockdown, nuclear fractionation, HR assay, immunofluorescence Cell Reports High 33789098
2024 BRCA1 promotes transcription of VDAC3 and GPX4; BRCA1 deficiency blocks VDAC3-dependent erastin-induced ferroptosis but sensitizes cells to GPX4 inhibitor-induced ferroptosis; NCOA4-mediated ferritinophagy and defective GPX4 induction synergize with PARP inhibition to induce ferroptosis in BRCA1-deficient cancers, revealing a dual regulatory role for BRCA1 in ferroptosis. siRNA/CRISPR knockdown, transcriptional reporter/ChIP, ferroptosis assays (cell viability, lipid peroxidation), xenograft tumor models, patient-derived xenograft Cancer Discovery Medium 38552003
2006 Loss of Brca1 in mouse T-cells results in telomere dysfunction including loss of telomere repeats and defective telomere capping; Brca1 synergizes with p53 deficiency to promote tumorigenesis with clonal chromosomal translocations arising from telomere dysfunction. Conditional knockout mouse model, telomere FISH, karyotyping, tumor incidence analysis Human Molecular Genetics Medium 16446310
2014 Neural progenitor-specific deletion of BRCA1 in developing mouse brain causes severe agenesis of neocortex, hippocampus, cerebellum, and olfactory bulbs primarily through excess p53-dependent apoptosis; centrosomal/cell polarity phenotypes are not rescued by p53 co-deletion but are partially rescued by ATM co-deletion, demonstrating distinct apoptotic and centrosomal functions of BRCA1 in neural progenitors. Conditional knockout mouse genetics, histology, p53 and ATM double-KO epistasis, immunofluorescence Proceedings of the National Academy of Sciences High 24639535

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science (New York, N.Y.) 5070 7545954
2009 Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England journal of medicine 2942 19553641
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2003 Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. American journal of human genetics 2611 12677558
2007 ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science (New York, N.Y.) 2519 17525332
1990 Linkage of early-onset familial breast cancer to chromosome 17q21. Science (New York, N.Y.) 2022 2270482
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
2000 A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Current biology : CB 1685 10959836
2003 Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science (New York, N.Y.) 1672 14576434
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet (London, England) 1415 20609467
2002 Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 1336 11832208
2007 Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1335 17416853
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
1997 Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 1278 9008167
2021 Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. The New England journal of medicine 1232 34081848
2009 Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature medicine 1144 19648928
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2010 Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet (London, England) 1109 20609468
1994 BRCA1 mutations in primary breast and ovarian carcinomas. Science (New York, N.Y.) 1107 7939630
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1999 Brca1 controls homology-directed DNA repair. Molecular cell 1018 10549283
2001 Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Molecular cell 1005 11239454
2002 Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. The New England journal of medicine 953 12023992
1999 RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 953 10500182
2007 RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 939 18001824
2000 BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes & development 898 10783165
1999 Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science (New York, N.Y.) 847 10550055
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