Affinage

BRCA2

Breast cancer type 2 susceptibility protein · UniProt P51587

Round 2 corrected
Length
3418 aa
Mass
384.2 kDa
Annotated
2026-04-28
130 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRCA2 is a tumor suppressor that functions as the central mediator of homologous recombination (HR) by loading RAD51 onto RPA-coated single-stranded DNA via its BRC repeats, stabilizing RAD51 nucleoprotein filaments by blocking ATP hydrolysis, and thereby enabling strand invasion for double-strand break repair (PMID:28, PMID:17). Independently of DSB repair, BRCA2 protects stalled replication forks from MRE11-mediated nucleolytic degradation through a separable C-terminal RAD51-stabilizing function, prevents R-loop accumulation at bivalent chromatin via interaction with ZFP281, and facilitates telomere replication during S/G2 phase (PMID:21565612, PMID:35715464, PMID:21076401). In mitosis, PLK1-mediated phosphorylation of BRCA2 at T207 scaffolds a PLK1–PP2A–BUBR1 complex that stabilizes kinetochore–microtubule attachments and ensures faithful chromosome segregation, while in meiosis the BRCA2–MEILB2–BRME1 ternary complex directs meiotic recombination essential for gametogenesis (PMID:32286328, PMID:32345962, PMID:14660434). Germline loss-of-function mutations in BRCA2 cause hereditary breast and ovarian cancer susceptibility and underlie Fanconi anemia complementation group D1, with BRCA2 deficiency creating a therapeutically exploitable synthetic lethality with PARP inhibition (PMID:8524414, PMID:12065746, PMID:19553641).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Linkage analysis in BRCA1-unlinked breast cancer families mapped a second susceptibility locus to 13q12-13, establishing that a second major hereditary breast cancer gene existed.

    Evidence Genomic linkage analysis in high-risk kindreds

    PMID:8091231

    Open questions at the time
    • Gene identity unknown
    • No protein product characterized
    • Penetrance and mutation spectrum undefined
  2. 1995 High

    Positional cloning identified BRCA2 as the 13q12-13 gene, with segregating truncating mutations in cancer families, resolving the gene's identity.

    Evidence Positional cloning and mutation screening in families

    PMID:8524414

    Open questions at the time
    • Full coding sequence incomplete
    • Protein function unknown
    • No biochemical activity defined
  3. 1997 High

    Discovery that BRCA2 physically interacts with RAD51 and that Brca2-null mouse embryos are radiation-hypersensitive established BRCA2 as a cofactor in RAD51-dependent DNA repair, providing the first mechanistic anchor.

    Evidence Co-immunoprecipitation of Brca2–Rad51 and mouse knockout with irradiation sensitivity

    PMID:9126738

    Open questions at the time
    • Biochemical mechanism of RAD51 regulation unknown
    • Whether BRCA2 directly loads RAD51 onto DNA untested
    • Role in specific repair pathways (HR vs others) unresolved
  4. 1998 High

    Targeted Brca2 truncation in mice revealed spontaneous chromosomal breaks, chromatid exchanges, and cell cycle arrest with p53/p21 activation, defining BRCA2 as essential for genome integrity maintenance.

    Evidence Mouse gene targeting with cytogenetics, genotoxic sensitivity assays, and cell cycle analysis

    PMID:9660919

    Open questions at the time
    • Whether genome instability arises from HR deficiency specifically or broader repair failure
    • Mechanism of centrosome amplification undefined
  5. 2002 High

    Identification of biallelic BRCA2 mutations in Fanconi anemia group D1 patients, with functional complementation restoring MMC resistance, unified the FA and BRCA DNA repair pathways.

    Evidence Mutation analysis and MMC complementation in FA-D1 cell lines

    PMID:12065746

    Open questions at the time
    • How BRCA2 connects to upstream FA pathway signaling unclear
    • Whether FANCD2 directly recruits BRCA2 untested
  6. 2004 High

    Monoubiquitinated FANCD2 was shown to promote BRCA2 loading into chromatin after damage, connecting the FA ubiquitination cascade to BRCA2-mediated repair and answering how BRCA2 is recruited to damage sites.

    Evidence Chromatin fractionation, co-IP, and immunofluorescence with truncated BRCA2 constructs

    PMID:15199141

    Open questions at the time
    • Whether interaction is direct or bridged by intermediates
    • Structural basis of FANCD2–BRCA2 interaction unknown
  7. 2005 High

    Electron microscopy of BRC peptide–RAD51 filament complexes revealed that different BRC repeats contact distinct RAD51 domains—BRC3 the N-terminal domain and BRC4 the nucleotide-binding core—and can stabilize or disrupt filaments concentration-dependently, establishing non-equivalence of BRC repeats.

    Evidence EM of RAD51-DNA filaments with BRC3/BRC4 peptide titrations

    PMID:15937124

    Open questions at the time
    • Full-length BRCA2 behavior on filaments not resolved
    • How eight BRC repeats coordinate in cis unknown
  8. 2006 High

    PALB2 was identified as a direct BRCA2 partner essential for BRCA2 chromatin localization, stability, and HR function—cancer-associated BRCA2 missense mutations disrupting PALB2 binding disabled HR, explaining how upstream regulation licenses BRCA2 activity.

    Evidence Co-IP, chromatin fractionation, HR reporter assay, and missense mutation analysis

    PMID:16793542

    Open questions at the time
    • Whether PALB2 bridges BRCA1 to BRCA2 not established in this study
    • Structural basis of PALB2–BRCA2 interface undefined
  9. 2006 High

    DSS1 was found to be constitutively bound to virtually all cellular BRCA2 and essential for BRCA2 protein stability, with DSS1 depletion causing BRCA2 degradation and DNA damage hypersensitivity, revealing a critical co-factor requirement.

    Evidence RNAi knockdown, co-IP, Western blot, and domain deletion in human cells

    PMID:16205630

    Open questions at the time
    • Mechanism by which DSS1 prevents degradation (proteasomal?) not fully defined
    • Whether DSS1 regulates BRCA2 oligomeric state in cells unknown at this point
  10. 2010 High

    Reconstitution with purified full-length human BRCA2 demonstrated it directly loads RAD51 onto ssDNA, displaces RPA, and stabilizes RAD51 filaments by blocking ATP hydrolysis—resolving the decade-old question of BRCA2's precise biochemical activity as a recombination mediator.

    Evidence In vitro RAD51 filament assembly, RPA displacement, and ATP hydrolysis assays with purified BRCA2

    PMID:20729832

    Open questions at the time
    • How BRCA2 oligomeric state affects mediator function in vivo
    • Structural mechanism of RPA displacement at atomic resolution unknown
  11. 2011 High

    BRCA2 was shown to protect stalled replication forks from MRE11-mediated degradation through a C-terminal RAD51-stabilizing site distinct from its RAD51-loading function, separating fork protection from DSB repair as an independent genome maintenance mechanism.

    Evidence Single-molecule DNA fiber analysis with BRCA2 domain mutants and MRE11 inhibition

    PMID:21565612

    Open questions at the time
    • How the fork protection vs. HR functions are regulated distinctly in vivo
    • Whether other nucleases besides MRE11 contribute to fork degradation in BRCA2-deficient cells
  12. 2016 High

    An ATM–UCHL3 phosphorylation–deubiquitination cascade was discovered to regulate RAD51 ubiquitination status, with only deubiquitinated RAD51 competent to bind BRCA2, revealing dynamic post-translational control of the BRCA2–RAD51 axis during the DNA damage response.

    Evidence In vitro kinase/deubiquitination assays, co-IP, RAD51 foci analysis, HR reporter

    PMID:27941124

    Open questions at the time
    • Identity of the RAD51 ubiquitin ligase unknown
    • Whether other DDR kinases contribute to UCHL3 activation untested
  13. 2020 High

    PLK1 phosphorylation of BRCA2 at T207 was shown to scaffold a PLK1–PP2A–BUBR1 complex at kinetochores, with disruption causing chromosome misalignment and aneuploidy, establishing a DNA-repair-independent mitotic function for BRCA2 in chromosome segregation.

    Evidence In vitro phosphorylation, NMR, co-IP, and chromosome alignment analysis with cancer variants S206C and T207A

    PMID:32286328

    Open questions at the time
    • How the mitotic function relates to BRCA2 tumor suppression quantitatively
    • Whether other mitotic kinases regulate BRCA2 at additional sites
  14. 2020 High

    Reconstitution of the BRCA2–MEILB2–BRME1 ternary complex and Brme1-knockout mice demonstrated that this complex directs meiotic DSB repair, synapsis, and crossover formation, explaining how BRCA2 is specifically deployed for meiotic recombination.

    Evidence Complex reconstitution, mouse knockout, immunofluorescence, and crossover quantification

    PMID:32345962

    Open questions at the time
    • Structural basis of the ternary complex unknown
    • Whether MEILB2-BRME1 modulates BRCA2 mediator activity biochemically untested
  15. 2020 High

    DSS1 and ssDNA were shown to counteract distinct modes of BRCA2 oligomerization (N-to-C and N-to-N terminal self-associations), providing a mechanistic framework for how BRCA2 transitions between oligomeric storage and active monomeric forms.

    Evidence Biochemical oligomerization assays with EM and DSS1/ssDNA competition experiments

    PMID:32609828

    Open questions at the time
    • Functional significance of distinct oligomeric states for HR in cells undefined
    • No high-resolution structure of full-length BRCA2 oligomer
  16. 2022 High

    ZFP281 was shown to recruit BRCA2 to bivalent chromatin in ESCs to suppress R-loop accumulation and replication stress, revealing a role for BRCA2 in transcription-replication conflict resolution beyond canonical DSB repair.

    Evidence Co-IP, ChIP-seq, S9.6 immunofluorescence, PCNA chromatin fractionation in ESCs

    PMID:35715464

    Open questions at the time
    • Whether BRCA2 resolves R-loops directly or via RAD51 loading unclear
    • Generality beyond ESCs and bivalent chromatin untested
  17. 2025 High

    Saturation genome editing of the entire BRCA2 DNA-binding domain classified nearly all possible single-nucleotide variants for pathogenicity, providing a comprehensive functional map linking DBD missense variants to cancer risk.

    Evidence CRISPR-Cas9 saturation mutagenesis in HAP1 cells with viability and HDR functional readout, ClinVar calibration

    PMID:39779857

    Open questions at the time
    • Exons 1–14 not covered in this study
    • Functional consequences of individual DBD missense variants on specific BRCA2 activities (fork protection, mitotic function) not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of full-length human BRCA2 exists; the coordination of eight BRC repeats during RAD51 loading in cis, the structural basis of BRCA2 oligomeric regulation, and the relative contributions of BRCA2's separable functions (HR, fork protection, mitosis, R-loop suppression) to tumor suppression remain unresolved.
  • Full-length BRCA2 structure unavailable
  • In vivo relative contributions of fork protection vs. HR vs. mitotic function to tumor suppression unquantified
  • Mechanism by which BRCA2 resolves R-loops at molecular level unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 2 GO:0044183 protein folding chaperone 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-1643685 Disease 4 R-HSA-1474165 Reproduction 3 R-HSA-69306 DNA Replication 3 R-HSA-1640170 Cell Cycle 2
Partners
DSS1FANCD2FANCGMEILB2PALB2PLK1RAD51ZFP281
Complex memberships
BRCA2-MEILB2-BRME1 meiotic complexBRCA2-PALB2-BRCA1 HR mediator complexBRCA2-PLK1-PP2A-BUBR1 mitotic complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 BRCA2 was localized to chromosome 13q12-13 by genomic linkage analysis in high-risk breast cancer families unlinked to BRCA1, establishing it as a second breast cancer susceptibility locus. Genetic linkage analysis Science High 8091231
1995 BRCA2 was identified as a gene on chromosome 13q12-13 in which germline frameshift and truncating mutations segregate with breast cancer in high-risk families, establishing it as the BRCA2 breast cancer susceptibility gene. Positional cloning, mutation screening Nature High 8524414
1996 The complete BRCA2 coding sequence and exonic structure were determined; BRCA2 is expressed ubiquitously and encodes a large protein; mutations causing truncation were identified in 13q-linked kindreds. cDNA sequencing, RT-PCR, mutation analysis Nature genetics High 8589730
1996 BRCA2 mRNA expression is cell cycle-regulated, with low levels in G0/early G1 and peak levels in late G1 and S phase, suggesting a role in cell proliferation. Northern blot analysis, cell cycle synchronization Cancer research Medium 8840967
1997 The mouse Brca2 protein physically interacts with the DNA-repair protein Rad51; Brca2-deficient mouse embryos show developmental arrest and radiation hypersensitivity, implicating Brca2 as an essential cofactor in Rad51-dependent repair of double-strand breaks. Co-immunoprecipitation, mouse knockout, embryo analysis, irradiation sensitivity assay Nature High 9126738
1997 BRCA2 mRNA is low in G0 and early G1, rises at the G1/S boundary, and remains elevated through S and G2/M phases, consistent with a function during DNA replication. Northern blot, cell cycle synchronization (MCF-10F and MCF-7 cells) Biochemical and biophysical research communications Medium 9168997
1998 Targeted truncation of murine Brca2 causes proliferative impediment, G1 and G2/M arrest with elevated p53 and p21, increased sensitivity to UV and MMS, and spontaneous chromosomal breaks and aberrant chromatid exchanges, defining Brca2 as essential for DNA repair. Mouse gene targeting, cell culture, genotoxic sensitivity assays, cytogenetics Molecular cell High 9660919
1998 BRCA2 protein forms in vivo complexes with both p53 and RAD51 in human cells; exogenous BRCA2 expression inhibits p53 transcriptional activity, and RAD51 co-expression enhances this inhibitory effect, linking BRCA2 to cell cycle control and DNA repair pathways. Co-immunoprecipitation, transient transfection, transcriptional reporter assay Proceedings of the National Academy of Sciences of the United States of America Medium 9811893
1999 Absence of Brca2 in mouse embryonic fibroblasts leads to frequent micronuclei formation through both loss of acentric chromosome fragments and chromosome missegregation, as well as centrosome amplification associated with micronuclei formation. Mouse hypomorphic mutant MEF culture, cytogenetic analysis, centrosome immunostaining Current biology Medium 10531007
1999 The BRCA2 promoter contains functional E-box and Ets/E2F binding sites; USF-1, USF-2 (as a heterodimer), and Elf-1 bind these sites and drive cell-cycle-regulated BRCA2 transcription; site-directed mutagenesis of either element reduces promoter activity. Promoter deletion analysis, EMSA, supershift assays, site-directed mutagenesis, co-transfection Oncogene Medium 10557089
2000 The C-terminal domain of BRCA2 contains two functional nuclear localization signals (NLS); mutations disrupting either NLS impair nuclear transport, providing a mechanism by which C-terminal truncating mutations cause nuclear mislocalization. GFP-fusion protein expression, fluorescence microscopy, site-directed mutagenesis in HeLa cells Biochemical and biophysical research communications Medium 10733923
2002 Cell lines from Fanconi anemia complementation groups B and D1 harbor biallelic mutations in BRCA2 and express truncated BRCA2 proteins; complementation with wild-type BRCA2 cDNA restores mitomycin C resistance, establishing BRCA2 as the FANCD1 gene and linking FA and BRCA pathways. Mutation analysis, Western blot, functional complementation (MMC resistance assay) Science High 12065746
2002 Brca2-deficient Chinese hamster V-C8 cells show hypersensitivity to DNA-damaging agents (especially interstrand cross-linkers), radioresistant DNA synthesis after ionizing radiation, chromosomal instability, abnormal centrosomes, and reduced nuclear RAD51 localization; complementation with human BRCA2 or mouse Brca2 rescues these defects. Cell complementation, sensitivity assays, cytogenetics, immunofluorescence Molecular and cellular biology High 11756561
2002 BRCA2 and Smad3 physically interact in vitro and in vivo; TGF-β1 stimulates interaction of endogenous Smad3 and BRCA2; BRCA2 co-activates Smad3-dependent transcriptional activation of PAI-1 and a luciferase reporter, revealing a role in TGF-β signaling. GST pulldown, co-immunoprecipitation, luciferase reporter assay, endogenous protein interaction Oncogene Medium 12165866
2003 BRCA2 deficiency in mice causes meiotic arrest of spermatocytes at early prophase I due to failure to complete recombination, despite initiation of DSB formation; in females, oocytes are depleted and show nuclear abnormalities. BRCA2 is thus essential for meiotic recombination in both sexes. Conditional mouse knockout (BAC rescue), histology, immunolocalization of recombination proteins Development High 14660434
2003 FANCG directly binds to BRCA2 at two sites flanking the BRC repeats as shown by yeast two-hybrid; FANCG co-immunoprecipitates with BRCA2 from human cells and co-localizes with BRCA2 and RAD51 in nuclear foci after mitomycin C treatment, directly connecting BRCA2 to the FA interstrand crosslink repair pathway. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization Human molecular genetics Medium 12915460
2004 Monoubiquitinated FANCD2 is required for targeting to chromatin, where it interacts with BRCA2 and promotes BRCA2 loading into chromatin complexes after DNA damage; the C-terminus of BRCA2 is required for functional interaction with FANCD2 in chromatin and for formation of co-localizing foci. Chromatin fractionation, co-immunoprecipitation, immunofluorescence, complementation with truncated BRCA2 constructs Molecular and cellular biology High 15199141
2005 BRCA2 BRC3 and BRC4 peptides bind RAD51-DNA nucleoprotein filaments at low molar ratios, stabilizing them; at high concentrations they disrupt filaments. BRC3 contacts the N-terminal domain of RAD51, while BRC4 contacts the nucleotide-binding core, demonstrating that different BRC repeats interact with distinct regions of RAD51. Electron microscopy of RAD51-DNA filaments, BRC peptide binding assays Proceedings of the National Academy of Sciences of the United States of America High 15937124
2005 BRCA2 subcellular localization and nuclear-cytoplasmic trafficking are regulated; BRCA2 is predominantly nuclear and its localization is linked to its DNA repair function; disruption of nuclear localization by certain mutations impairs genome maintenance. Subcellular fractionation, immunofluorescence, review of transport mechanisms BioEssays Low 16108063
2006 PALB2 was identified as a BRCA2 binding protein that colocalizes with BRCA2 in nuclear foci, promotes BRCA2 localization and stability in chromatin and nuclear matrix, and enables BRCA2's homologous recombination and checkpoint functions; germline BRCA2 missense mutations that disrupt PALB2 binding disable BRCA2 HR function. Co-immunoprecipitation, immunofluorescence, chromatin fractionation, HR reporter assay, missense mutation analysis Molecular cell High 16793542
2006 Essentially all BRCA2 in human cell lines is associated with DSS1; RNAi knockdown of DSS1 leads to dramatic loss of BRCA2 protein through increased degradation; deletion of the DSS1-binding domain of BRCA2 renders BRCA2 stability insensitive to DSS1 depletion; DSS1 depletion also causes hypersensitivity to DNA damage. Western blot, RNAi knockdown, co-immunoprecipitation, DNA damage sensitivity assay Oncogene High 16205630
2007 Drosophila BRCA2 ortholog (dmbrca2) physically interacts with dmRAD51 (spnA) and both are recruited to nuclear foci after DNA damage; depletion of dmbrca2 confers sensitivity to irradiation and hydroxyurea, and impairs double-strand break repair by gene conversion; dmbrca2 depletion is synthetically lethal with dmparp deficiency. Co-immunoprecipitation, immunofluorescence, RNAi depletion, DR-white gene conversion assay, synthetic lethality DNA repair High 17822964
2007 Neural-specific inactivation of Brca2 profoundly impairs neurogenesis, causing extensive DNA damage (γH2AX) in neural tissue; p53 deficiency rescues brain histology but leads to medulloblastoma; ATM loss partially restores cerebellar morphology, placing Brca2 downstream of an ATM-independent genomic surveillance pathway during neurogenesis. Conditional knockout (Nestin-Cre), histology, γH2AX immunostaining, genetic epistasis with p53 and Atm The EMBO journal High 17476307
2008 PARP-1 binds to a silencer region (−582 to −516) of the BRCA2 promoter in vitro and in vivo (ChIP); PARP-1 inhibition or siRNA knockdown increases endogenous BRCA2 expression; inhibition of PARP-1 activity reduces histone H3K9 acetylation and blocks PARP-1 promoter binding, identifying PARP-1 as a transcriptional repressor of BRCA2. Affinity purification, mass spectrometry, EMSA, ChIP, siRNA, PARP inhibitor treatment The Journal of biological chemistry High 18990703
2008 PARP inhibitor resistance in BRCA2-deficient CAPAN1 cells arises from intragenic deletion that corrects the BRCA2 reading frame, restoring partial BRCA2 function, RAD51 focus formation, and homologous recombination; similar reversion mutations occur in carboplatin-resistant ovarian tumors from BRCA2 mutation carriers. Drug resistance clonal analysis, sequencing, Western blot, RAD51 immunofluorescence, HR assay, tumor sequencing Nature High 18264088
2009 PARP inhibitor olaparib shows antitumor activity selectively in BRCA1/BRCA2 mutation carriers (ovarian, breast, prostate cancer), demonstrating synthetic lethality between PARP inhibition and BRCA2 deficiency in human tumors; pharmacodynamic studies confirmed PARP inhibition in tumor tissue. Phase 1 clinical trial with pharmacokinetic/pharmacodynamic analysis and tumor biopsies The New England journal of medicine High 19553641
1999 ATR specifically phosphorylates a BRCA2 peptide in vitro, while ATM phosphorylates BRCA1 peptides, identifying BRCA2 as a putative ATR substrate at SQ/TQ motifs. In vitro kinase assay with GST-peptide substrates The Journal of biological chemistry Low 10608806
2007 Large-scale phosphoproteomic analysis identified BRCA2 among >700 proteins phosphorylated on ATM/ATR consensus (SQ/TQ) sites in response to DNA damage, placing BRCA2 within the DNA damage response signaling network. Immunoaffinity phosphopeptide enrichment, mass spectrometry Science Medium 17525332
2010 Purified full-length human BRCA2 binds RAD51 and promotes RAD51 assembly onto ssDNA over dsDNA, displaces RPA from ssDNA, and stabilizes RAD51-ssDNA filaments by blocking ATP hydrolysis; BRCA2 does not anneal RPA-coated ssDNA, showing it does not function in ssDNA annealing-based repair. Protein purification, in vitro RAD51 filament assembly assay, RPA displacement assay, ATP hydrolysis assay Nature High 20729832
2010 BRCA2 associates with telomeres during S and G2 phases and loads RAD51 onto telomeres; conditional deletion of Brca2 or inhibition of Rad51 (but not Brca1 loss) causes telomere shortening and fragile telomere signals indicative of replication defects, showing BRCA2-mediated HR contributes to telomere replication and maintenance. ChIP, immunofluorescence-FISH, conditional MEF knockout, TIF analysis, telomere length measurement Nature structural & molecular biology High 21076401
2010 brca2 is required for ovarian development in zebrafish; brca2(Q658X) homozygous fish fail to develop ovaries during sex differentiation and undergo female-to-male sex reversal with meiotic arrest in spermatocytes; tp53 mutation rescues ovarian development; adult brca2 mutants develop testicular neoplasias. Zebrafish nonsense mutant, histology, genetic epistasis with tp53 Proceedings of the National Academy of Sciences of the United States of America High 20974951
2011 BRCA2 protects stalled replication forks from nucleolytic degradation by MRE11 independently of its role in DSB repair by HDR: a conserved C-terminal RAD51-stabilizing site (distinct from the RAD51-loading function) is essential for fork protection; RAD51 filament disruption phenocopies BRCA2 deficiency and MRE11 inhibition rescues chromosomal aberrations. Single-molecule DNA fiber analysis, BRCA2 mutational analysis, MRE11 inhibition, genetic epistasis Cell High 21565612
2011 zebrafish brca2 mutant oocytes show polarized rather than symmetrical nuclear architecture (nucleoli and chromosomes distributed to opposite nuclear poles), revealing a novel role for Brca2 in establishing oocyte nuclear architecture; tp53 mutation rescues sex reversal but not spermatogenesis, showing brca2 is essential for zebrafish spermatogenesis through a p53-independent mechanism. Zebrafish insertional mutant, immunofluorescence, in situ hybridization, genetic epistasis with tp53 PLoS genetics High 21483806
2012 FA genes FANCD2 and BRCA1 are required for protecting stalled replication forks from degradation in a pathway epistatic with RAD51; elevated RAD51 levels or stabilized RAD51 filaments rescue fork protection in FANCD2-deficient cells, defining a unified fork protection pathway connecting FA genes to RAD51 and BRCA1/2. DNA fiber analysis, RAD51 overexpression/stabilization, siRNA epistasis Cancer cell High 22789542
2012 Leishmania infantum BRCA2 (LiBRCA2) interacts with LiRAD51; BRCA2 null mutants show genomic instability, gene-targeting defects, and loss of nuclear RAD51 localization; purified LiBRCA2 stimulates RAD51-mediated D-loop formation on ssDNA, establishing BRCA2 as a recombination mediator in Leishmania. Gene disruption, co-immunoprecipitation, in vitro D-loop assay, cytological RAD51 localization Nucleic acids research High 22505581
2013 BRCA2 is epistatic to each of the four RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2) tested in human cells: loss of BRCA2 alone is more severe than loss of any single paralog, and combined knockdown does not worsen BRCA2 deficiency, placing BRCA2 downstream of or parallel to the RAD51 paralogs in HR. siRNA-mediated knockdown, epistasis analysis, DNA damage response assays in human cells DNA repair Medium 23384538
2016 In response to DNA damage, ATM phosphorylates and activates the deubiquitinase UCHL3, which deubiquitinates RAD51; ubiquitinated RAD51 cannot bind BRCA2, while deubiquitinated RAD51 efficiently binds BRCA2 and is recruited to DSBs. This phosphorylation-deubiquitination cascade dynamically regulates the BRCA2-RAD51 axis in HR. Co-immunoprecipitation, in vitro deubiquitination assay, ATM kinase assay, RAD51 foci analysis, HR reporter assay Genes & development High 27941124
2018 Two sisters with compound heterozygous truncating BRCA2 mutations had reduced BRCA2 protein, impaired DNA damage response, chromosomal breakage, failure of RAD51 recruitment to DSBs, and XX ovarian dysgenesis; Drosophila null mutants for the BRCA2 ortholog were sterile with gonadal dysgenesis in both sexes, establishing an essential role for BRCA2 in ovarian development. Patient genetic analysis, functional DNA damage assay (RAD51 foci), Drosophila genetic model The New England journal of medicine High 30207912
2019 Genome-wide CRISPR/shRNA screens in BRCA2-isogenic cell lines identified APEX2 and FEN1 as synthetic lethal genes with BRCA2 loss: BRCA2-deficient cells require the apurinic endonuclease activity and PCNA-binding domain of APEX2 (but not APEX1), and require the 5' flap endonuclease (but not exonuclease) activity of FEN1; FEN1 participates in MMEJ as a collateral repair pathway when HR is deficient. shRNA and CRISPR genetic screens, isogenic cell line pairs, domain-specific rescue constructs, MMEJ reporter assay Molecular cell High 30686591
2020 BRCA2 is phosphorylated by PLK1 at T207, creating a docking site for PLK1; BRCA2 bound to PLK1 forms a complex with PP2A and phospho-BUBR1; BRCA2 variants S206C and T207A reduce PLK1 binding, destabilize this tetrameric complex, cause unstable kinetochore-microtubule interactions, chromosome misalignment, faulty segregation, and aneuploidy, revealing a mitotic role for BRCA2 distinct from DNA repair. In vitro phosphorylation assay, Co-immunoprecipitation, NMR, immunofluorescence, chromosome alignment analysis Nature communications High 32286328
2020 BRCA2 binds MEILB2 at its C-terminus to form the BRCA2-MEILB2-BRME1 ternary complex; BRME1 stabilizes MEILB2 by binding its α-helical N-terminus and preventing MEILB2 self-association; in Brme1-/- mice, the BRCA2-MEILB2 complex is destabilized, causing defects in meiotic DSB repair, homolog synapsis, and crossover formation; ectopic MEILB2-BRME1 expression in somatic cancer cells impairs mitotic HR. Biochemical complex reconstitution, mouse knockout, immunofluorescence, crossover analysis, HR assay in cancer cells Nature communications High 32345962
2020 DSS1 and ssDNA counteract BRCA2 oligomerization: BRCA2 self-associates through N-to-C terminal and N-to-N terminal interactions; DSS1 disrupts the N-to-C terminal self-interaction independently of RPA; ssDNA modulates N-to-N terminal self-interaction; defining distinct monomeric and oligomeric BRCA2 assemblies with potentially different functional roles. Biochemical oligomerization assay, electron microscopy, DSS1/ssDNA competition experiments, domain mapping Nucleic acids research High 32609828
2022 ZFP281 interacts with BRCA2 and recruits it to G/C-rich bivalent chromatin regions in embryonic stem cells; depletion of ZFP281 or BRCA2 causes R-loop accumulation over bivalent regions and impairs DNA replication (reduced PCNA on chromatin); this mechanism suppresses R-loop-mediated replication stress and enables proper developmental gene activation. Co-immunoprecipitation, ChIP-seq, R-loop immunofluorescence (S9.6), PCNA chromatin fractionation, siRNA knockdown Nature communications High 35715464
2025 Saturation genome editing of all possible single-nucleotide variants in BRCA2 exons 15–26 (DNA-binding domain) using CRISPR-Cas9 in HAP1 cells classified 6,959/6,960 variants into pathogenicity categories; loss-of-function missense variants in the DBD are associated with increased breast and ovarian cancer risk, and 91% of variants could be classified as pathogenic/likely pathogenic or benign/likely benign. Saturation genome editing (CRISPR-Cas9 endogenous knock-in), HAP1 haploid cell viability assay, HDR functional assay, Bayesian VarCall model, ClinVar calibration Nature High 39779857

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England journal of medicine 2942 19553641
1995 Identification of the breast cancer susceptibility gene BRCA2. Nature 2815 8524414
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
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
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
2003 Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science (New York, N.Y.) 1672 14576434
1994 Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science (New York, N.Y.) 1513 8091231
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 1333 17416853
1999 Cancer risks in BRCA2 mutation carriers. Journal of the National Cancer Institute 1162 10433620
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
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2011 Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 1061 21565612
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2002 Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. The New England journal of medicine 953 12023992
1997 Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 917 9126738
2002 Biallelic inactivation of BRCA2 in Fanconi anemia. Science (New York, N.Y.) 913 12065746
2013 Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nature genetics 895 23535729
2004 Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 837 15367553
2008 Resistance to therapy caused by intragenic deletion in BRCA2. Nature 830 18264088
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2012 A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer cell 796 22789542
2003 Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. Journal of the National Cancer Institute 743 14519755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1996 The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nature genetics 696 8589730
2004 BRCA1 and BRCA2: 1994 and beyond. Nature reviews. Cancer 690 15343273
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