{"gene":"BRCA2","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2002,"finding":"Crystal structure of a ~90 kDa BRCA2 C-terminal domain bound to DSS1 reveals three OB folds and a helix-turn-helix (HTH) motif; the domain binds single-stranded DNA (ssDNA) via the OB folds; the HTH motif is implicated in dsDNA binding; and this BRCA2 domain stimulates RAD51-mediated recombination in vitro.","method":"X-ray crystallography (3.1 Å apo structure; 3.5 Å ssDNA-bound structure), in vitro DNA-binding assays, in vitro RAD51 recombination stimulation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures at atomic resolution combined with biochemical recombination assay; multiple orthogonal methods in a single rigorous study","pmids":["12228710"],"is_preprint":false},{"year":2010,"finding":"Full-length purified human BRCA2 binds RAD51 and promotes assembly of RAD51 onto ssDNA over dsDNA, displaces RPA from ssDNA, and stabilizes RAD51-ssDNA filaments by blocking ATP hydrolysis; BRCA2 does not anneal RPA-coated ssDNA, indicating it does not function in ssDNA-annealing repair pathways.","method":"Purification of full-length human BRCA2, in vitro RAD51 binding, ssDNA/dsDNA competition assays, RPA displacement assay, ATPase assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with full-length purified protein, multiple orthogonal biochemical assays in one rigorous study","pmids":["20729832"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure and structure-guided mutagenesis reveal that the BRCA2 TR2 motif at the C-terminus binds across the protomer interface of the RAD51 nucleoprotein filament, acting as a molecular brace for adjacent RAD51 molecules and stabilizing the filament; TR2 targets an acidic-patch motif on human RAD51.","method":"Cryo-electron microscopy, structure-guided mutagenesis","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure combined with mutagenesis validation in a single study","pmids":["37919288"],"is_preprint":false},{"year":2023,"finding":"Single-molecule visualization shows that BRCA2 accelerates RAD51 nucleation on RPA-coated ssDNA to rates approaching association with naked ssDNA, overcoming the kinetic barrier imposed by RPA; a dimer of RAD51 is minimally required for spontaneous nucleation; BRCA2 can chaperone a preassembled short RAD51 filament onto RPA-coated ssDNA.","method":"Microfluidics, single-molecule fluorescence microscopy, micromanipulation of individual DNA molecules","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule reconstitution with full-length BRCA2, multiple quantitative measurements in one rigorous study","pmids":["36976771"],"is_preprint":false},{"year":2005,"finding":"BRCA2 BRC repeats (BRC3 and BRC4) bind RAD51-DNA nucleoprotein filaments at low molar ratios, with BRC3 contacting the N-terminal domain of RAD51 and BRC4 contacting the nucleotide-binding core; at high concentrations the BRC repeats disrupt filaments. The eight BRC repeats are non-equivalent in their mode of RAD51 interaction.","method":"Electron microscopy of RAD51-DNA filaments incubated with BRC peptides, protein-protein interaction mapping","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EM structural analysis with BRC repeat peptides, two orthogonal interaction-mapping approaches, single lab","pmids":["15937124"],"is_preprint":false},{"year":2016,"finding":"BRCA2 BRC repeats interact directly with the meiosis-specific recombinase DMC1; BRC1-3 bind RAD51 preferentially while BRC6-8 bind DMC1 preferentially; individual BRC repeats (except BRC4) stimulate DMC1-ssDNA complex formation; full-length BRCA2 stimulates DMC1-mediated DNA strand exchange between RPA-ssDNA and duplex DNA, identifying BRCA2 as a mediator of DMC1 recombination.","method":"In vitro BRC repeat-DMC1 binding assays, DNA strand exchange assay with purified full-length BRCA2, RPA-ssDNA competition assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with full-length BRCA2, multiple biochemical assays demonstrating DMC1 mediator function","pmids":["26976601"],"is_preprint":false},{"year":1998,"finding":"BRCA2 is a ~460 kDa nuclear phosphoprotein that forms in vivo complexes with both p53 and RAD51; exogenous BRCA2 expression inhibits p53 transcriptional activity, and RAD51 co-expression enhances this inhibitory effect.","method":"Co-immunoprecipitation from human cells, transient transfection/transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and functional transcriptional assay, two orthogonal methods but single lab","pmids":["9811893"],"is_preprint":false},{"year":1998,"finding":"Cells with a targeted truncation of murine Brca2 show proliferative impediment, G1 and G2/M arrest with elevated p53/p21, hypersensitivity to UV and MMS, spontaneous chromosomal breaks and aberrant chromatid exchanges, establishing Brca2 function in DNA repair.","method":"Mouse gene targeting (Brca2 truncation), colony survival assays, cell cycle analysis, cytogenetics","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts; foundational study replicated broadly","pmids":["9660919"],"is_preprint":false},{"year":2009,"finding":"BRCA1 associates with BRCA2 through PALB2/FANCN; in PALB2-deficient cells the BRCA1-BRCA2 interaction is abrogated; BRCA1 promotes concentration of PALB2 and BRCA2 at DNA-damage sites; the BRCA1-PALB2 interaction is required for homologous recombination repair, placing BRCA1 upstream of BRCA2 in the DNA-damage response.","method":"Co-immunoprecipitation, siRNA depletion, laser-microirradiation focus recruitment assay, HR reporter assay","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, depletion rescue, functional HR assay; multiple orthogonal methods in one study","pmids":["19268590"],"is_preprint":false},{"year":2004,"finding":"Monoubiquitination of FANCD2 (activated by DNA damage) is required for targeting FANCD2 to chromatin where it interacts with BRCA2 and promotes BRCA2 chromatin loading; the C-terminus of BRCA2 is required for functional colocalization of BRCA2 and FANCD2 in chromatin complexes.","method":"Chromatin fractionation, co-immunoprecipitation, immunofluorescence focus assays, complementation with wild-type BRCA2 cDNA in BRCA2-deficient cells","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — chromatin fractionation, co-IP, focus assays and functional complementation; multiple orthogonal approaches in one study","pmids":["15199141"],"is_preprint":false},{"year":2003,"finding":"FANCG directly binds BRCA2 at two separate sites flanking the BRC repeats (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.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus confirmatory co-IP and co-localization, two orthogonal methods in one lab","pmids":["12915460"],"is_preprint":false},{"year":2003,"finding":"EMSY protein binds BRCA2 within an exon 3-encoded region deleted in cancer, silences the transcriptional activation potential of BRCA2 exon 3, associates with chromatin regulators HP1β and BS69, and localizes to sites of DNA repair following DNA damage.","method":"Co-immunoprecipitation/pulldown, transcriptional reporter assay, immunofluorescence","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding and functional silencing assays plus damage localization, single lab with multiple methods","pmids":["14651845"],"is_preprint":false},{"year":2002,"finding":"BRCA2 deficiency in XRCC11-complementation group hamster cells (V-C8) causes radioresistant DNA synthesis (checkpoint defect), extreme sensitivity to interstrand crosslinking agents, chromosomal instability, abnormal centrosomes, and reduced nuclear localization of RAD51.","method":"Chromosome 13 complementation, Brca2 cDNA complementation, clonogenic survival assays, cytogenetics, immunofluorescence for Rad51 localization","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic complementation plus multiple cellular phenotype readouts establishing BRCA2/XRCC11 identity and RAD51 localization dependence","pmids":["11756561"],"is_preprint":false},{"year":2017,"finding":"Reversed replication forks are entry points for nucleolytic fork degradation in BRCA2-defective cells; MRE11, PTIP, and RAD52 promote stalled fork degradation and chromosomal breakage in BRCA2-deficient cells; impairing fork reversal prevents fork degradation but increases chromosomal breakage; BRCA2 assembles stable RAD51 nucleofilaments on regressed arms to protect them from degradation.","method":"DNA fiber spreading, direct visualization of replication intermediates (electron microscopy), genetic inactivation of fork-reversal and degradation factors","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — fiber spreading and EM imaging of replication intermediates, multiple genetic perturbations, clean mechanistic dissection in one study","pmids":["29038466"],"is_preprint":false},{"year":2020,"finding":"PLK1 phosphorylates BRCA2 at a conserved T207 site in mitosis, creating a PLK1 docking site; BRCA2 bound to PLK1 forms a complex with phosphatase PP2A and phosphorylated BUBR1; breast cancer variants S206C and T207A reduce BRCA2-PLK1 binding, destabilize this tetrameric complex, and cause unstable kinetochore-microtubule interactions, misaligned chromosomes, and aneuploidy.","method":"In vitro phosphorylation assay, co-immunoprecipitation, NMR structure of phosphopeptide, chromosomal alignment assays in cells expressing BRCA2 variants","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical phosphorylation, co-IP, structural characterization of phosphopeptide, and cellular phenotypic validation; multiple orthogonal methods","pmids":["32286328"],"is_preprint":false},{"year":2021,"finding":"ATM and ATR kinases phosphorylate a conserved region in BRCA2 in response to DSBs; these phosphorylations recruit the phosphatase PP2A-B56 to BRCA2 via a conserved binding motif; the BRCA2-PP2A-B56 complex is required for efficient RAD51 filament formation at DNA damage sites and HR-mediated repair; cancer-associated BRCA2 mutations that deregulate this interaction sensitize cells to PARP inhibition.","method":"Phosphoproteomics, co-immunoprecipitation, HR assay, PARP inhibitor sensitivity assay, mutagenesis of PP2A-binding motif","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, functional HR assay, drug sensitivity, and mutagenesis; multiple orthogonal methods in one study","pmids":["34593815"],"is_preprint":false},{"year":2018,"finding":"BRCA2 directly interacts with RNase H2 and mediates RNase H2 localization to DSBs specifically in S/G2 phase, controlling DNA:RNA hybrid (R-loop) levels at DSBs; damage-induced lncRNAs contribute to recruitment of BRCA1, BRCA2, and RAD51 to DSBs without affecting DNA-end resection.","method":"Co-immunoprecipitation, laser-microirradiation and focus assay, DNA:RNA hybrid immunoprecipitation (DRIP), cell-cycle-staged analysis","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional localization assay and DRIP, single lab with two orthogonal approaches","pmids":["30560944"],"is_preprint":false},{"year":2017,"finding":"Formaldehyde selectively depletes BRCA2 via proteasomal degradation; heterozygous BRCA2 truncations sensitize cells to BRCA2 haploinsufficiency induced by formaldehyde or acetaldehyde, causing replication fork stalling, chromosomal aberrations, and R-loop accumulation; Ribonuclease H1 ameliorates these replication defects, linking BRCA2 inactivation to spontaneous mutagenesis via aberrant RNA-DNA hybrids.","method":"Western blot for BRCA2 protein levels after aldehyde treatment, proteasome inhibitor rescue, DNA fiber assay, cytogenetics, RNase H1 overexpression rescue","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteolysis assay, fiber analysis, genetic rescue) establishing mechanism in one study","pmids":["28575672"],"is_preprint":false},{"year":2019,"finding":"HSF2BP interacts with a specific 68-amino acid region of BRCA2 (Gly2270–Thr2337, between BRC repeats and the DNA-binding domain) via armadillo repeats; this interaction is constitutive in mouse embryonic stem cells; Hsf2bp knockout mice are male infertile due to a severe HR defect during spermatogenesis.","method":"Co-immunoprecipitation, yeast two-hybrid domain mapping, mouse knockout, meiotic HR assay","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP domain mapping, mouse knockout phenotype, single lab with two orthogonal methods","pmids":["31242413"],"is_preprint":false},{"year":2020,"finding":"BRCA2 forms a ternary complex with MEILB2 and BRME1 in meiosis; BRME1 stabilizes MEILB2 by preventing its self-association; BRCA2 binds the C-terminus of MEILB2; Brme1 knockout mice show defects in DSB repair, homolog synapsis, and crossover formation; ectopic expression of MEILB2-BRME1 in somatic cancer cells impairs mitotic HR.","method":"Co-immunoprecipitation, mouse knockout, immunofluorescence for DSB repair proteins, HR assay in somatic cells","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mouse KO phenotype, and functional HR assay; single lab with multiple methods","pmids":["32345962"],"is_preprint":false},{"year":2020,"finding":"DSS1 and ssDNA counteract BRCA2 oligomerization; three self-interacting regions and two types of self-association (N-to-C and N-to-N terminal) were identified; the N-to-C interaction is sensitive to DSS1 and ssDNA, while the N-to-N interaction is modulated by ssDNA; defining a regulatory mechanism for BRCA2 oligomeric state.","method":"Biochemical pulldown assays, electron microscopic imaging of BRCA2 complexes, domain mapping","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical pulldown and EM imaging, single lab, two orthogonal methods","pmids":["32609828"],"is_preprint":false},{"year":2022,"finding":"ZFP281 interacts with BRCA2 and is required for BRCA2 recruitment to bivalent chromatin (with PRC2); depletion of ZFP281 or BRCA2 causes R-loop accumulation over bivalent regions and impairs DNA replication progression; ZFP281 cooperates with BRCA2 to prevent persistent R-loops at G/C-rich promoters.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), DRIP (DNA:RNA hybrid immunoprecipitation), DNA replication assay, siRNA depletion","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, DRIP, and functional replication assay; single lab with multiple orthogonal methods","pmids":["35715464"],"is_preprint":false},{"year":2024,"finding":"The glycolytic metabolite methylglyoxal (MGO) triggers BRCA2 proteolysis, transiently disabling BRCA2 tumor suppressive functions in DNA repair and replication and causing functional haploinsufficiency; this generates a cancer-associated mutational signature (SBS) in non-malignant mammary cells without biallelic BRCA2 inactivation; BRCA2 monoallelic mutations predispose to these changes.","method":"Protein stability assays (western blot after MGO treatment), mutational signature analysis, patient-derived organoids, mouse models, proteasome inhibitor rescue","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteolysis assay, organoid and mouse model validation, mutational signature analysis; multiple orthogonal methods in one study","pmids":["38608703"],"is_preprint":false},{"year":2008,"finding":"PARP-1 binds a silencer region (-582 to -516) of the BRCA2 promoter in vitro and in vivo and down-regulates BRCA2 expression; PARP-1 inhibitors or PARP-1 siRNA increase endogenous BRCA2 expression; inhibition of PARP-1 activity reduces histone H3K9 acetylation and blocks PARP-1 binding to the BRCA2 promoter.","method":"Affinity purification and mass spectrometry, EMSA (gel shift), antibody super-shift, chromatin immunoprecipitation (ChIP), PARP-1 siRNA knockdown, PARP inhibitor treatment","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, EMSA, and functional knockdown experiments; single lab with multiple orthogonal methods","pmids":["18990703"],"is_preprint":false},{"year":2005,"finding":"BRCA2 binds and stabilizes MAGE-D1 protein; BRCA2 and MAGE-D1 synergistically suppress cell proliferation independently of the p53 pathway; MAGE-D1 expression is required for BRCA2-mediated suppression of cell proliferation (shown by RNAi), establishing MAGE-D1 as a downstream effector of BRCA2 in growth suppression.","method":"Co-immunoprecipitation, RNAi knockdown, cell proliferation assay, western blot","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP, RNAi epistasis, and proliferation assay; single lab with multiple methods","pmids":["15930293"],"is_preprint":false},{"year":2006,"finding":"FANCC gene disruption in brca2ΔCTD (C-terminal domain truncation) cells reveals epistasis between FANCC and the BRCA2 CTD for X-ray sensitivity; however, combined fancc/brca2ΔCTD cells show additive sensitivity to cisplatin and increased MMC-induced chromosomal aberrations relative to either single mutant, indicating the FA pathway has a CTD-independent role in interstrand crosslink repair separate from BRCA2-RAD51-mediated HR.","method":"Conditional gene targeting (brca2ΔCTD), FANCC disruption, clonogenic survival assays, cytogenetics","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double-mutant epistasis analysis with genetic complementation; single lab with well-defined genetic dissection","pmids":["16687415"],"is_preprint":false},{"year":2017,"finding":"In non-transformed human mammary epithelial cells, BRCA2 loss causes replication stress associated with DNA under-replication, leading to mitotic abnormalities, 53BP1 nuclear body formation in the subsequent G1 phase, and G1 arrest; the HR function of BRCA2 (not stalled-fork protection) is primarily responsible for supporting cell viability in this context.","method":"CRISPR-Cas9 conditional BRCA2 knockout in human mammary epithelial cells, DNA fiber assay, immunofluorescence (53BP1 nuclear bodies, γH2AX), cell cycle analysis","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple orthogonal readouts (fiber analysis, immunofluorescence, cell cycle) mechanistically dissecting HR vs. fork-protection functions","pmids":["28904335"],"is_preprint":false}],"current_model":"BRCA2 is a central mediator of homologous recombination (HR) that directly binds ssDNA through OB-fold domains and uses eight BRC repeats plus a C-terminal TR2 motif to load and stabilize RAD51 (and meiotic DMC1) nucleoprotein filaments on RPA-coated ssDNA, thereby driving error-free repair of DNA double-strand breaks; beyond HR, BRCA2 protects reversed replication forks from MRE11-mediated nucleolytic degradation via stable RAD51 filament assembly on regressed arms, controls DNA:RNA hybrid levels at DSBs by recruiting RNase H2, links BRCA1 to the HR machinery through the PALB2 scaffold, participates in mitotic chromosome alignment through a PLK1-T207 phosphorylation-dependent complex with PP2A-B56 and BUBR1, and its activity is regulated by ATM/ATR phosphorylation, PP2A-B56, DSS1-mediated monomerization, and PARP-1-mediated transcriptional repression—with loss of these functions leading to replication stress, chromosomal instability, and cancer predisposition."},"narrative":{"mechanistic_narrative":"BRCA2 is a central mediator of homologous recombination (HR) that loads and stabilizes the RAD51 recombinase on resected DNA to drive error-free repair of double-strand breaks, with loss of function producing chromosomal instability, checkpoint defects, and crosslinker hypersensitivity [PMID:9660919, PMID:11756561]. A large C-terminal domain binds single-stranded DNA through three OB folds (with an HTH motif implicated in dsDNA binding) and stimulates RAD51-mediated recombination in vitro [PMID:12228710]. Full-length BRCA2 binds RAD51 and selectively assembles it onto ssDNA over dsDNA, displaces RPA, and stabilizes the resulting filament by blocking RAD51 ATP hydrolysis [PMID:20729832]; at the molecular level it accelerates RAD51 nucleation on RPA-coated ssDNA to rates approaching those on naked ssDNA, overcoming the kinetic barrier RPA imposes [PMID:36976771]. The eight BRC repeats engage RAD51 non-equivalently to control filament assembly versus disruption [PMID:15937124], while the C-terminal TR2 motif braces adjacent RAD51 protomers across the filament interface via an acidic-patch contact [PMID:37919288]. BRCA2 is brought to damage sites through the BRCA1–PALB2 axis, which places BRCA1 upstream of BRCA2 in HR [PMID:19268590], and through FANCD2/Fanconi-pathway interactions that promote its chromatin loading [PMID:15199141, PMID:12915460]. Beyond canonical HR, BRCA2 protects reversed replication forks from MRE11-, PTIP-, and RAD52-mediated nucleolytic degradation by assembling stable RAD51 filaments on regressed arms [PMID:29038466], and it limits DNA:RNA hybrid (R-loop) accumulation at breaks and at G/C-rich chromatin by recruiting RNase H2 in S/G2 phase [PMID:30560944, PMID:35715464]. Its activity is governed by phosphoregulation and proteostasis: ATM/ATR phosphorylation recruits PP2A-B56 to promote RAD51 filament formation [PMID:34593815], a PLK1-T207 phosphorylation event builds a PP2A–BUBR1 complex required for mitotic chromosome alignment [PMID:32286328], DSS1 and ssDNA control BRCA2 oligomeric state [PMID:32609828], and reactive metabolites such as formaldehyde and methylglyoxal trigger its proteasomal degradation to cause transient functional haploinsufficiency and mutagenesis [PMID:28575672, PMID:38608703]. BRCA2 additionally functions as a meiotic recombination mediator, stimulating DMC1 strand exchange through DMC1-preferring BRC repeats and acting within meiosis-specific complexes [PMID:26976601, PMID:31242413, PMID:32609828].","teleology":[{"year":1998,"claim":"Established that BRCA2 is a nuclear protein physically and functionally linked to the recombination and tumor-suppression machinery, by showing in vivo complexes with RAD51 and p53 and a DNA-repair phenotype upon disruption.","evidence":"Co-IP and transcriptional reporter assays in human cells; murine Brca2 truncation with survival, cell-cycle, and cytogenetic readouts","pmids":["9811893","9660919"],"confidence":"High","gaps":["Did not define the biochemical mechanism of RAD51 regulation","p53 transcriptional effect not mapped to a direct molecular activity"]},{"year":2002,"claim":"Defined the structural basis of BRCA2 DNA engagement by resolving the DSS1-bound C-terminal domain with three OB folds that bind ssDNA and demonstrating it stimulates RAD51 recombination in vitro.","evidence":"X-ray crystallography (apo and ssDNA-bound) with in vitro DNA-binding and recombination assays","pmids":["12228710"],"confidence":"High","gaps":["Used a domain fragment rather than full-length protein","Did not show how RPA-coated ssDNA is handled in cells"]},{"year":2002,"claim":"Linked BRCA2 deficiency directly to RAD51 nuclear localization and genome stability by identifying BRCA2 as the XRCC11 gene and characterizing crosslinker sensitivity, checkpoint defects, and centrosome abnormalities.","evidence":"Chromosome and cDNA complementation of V-C8 hamster cells with survival, cytogenetic, and RAD51 localization assays","pmids":["11756561"],"confidence":"High","gaps":["Did not separate HR from fork-protection contributions to instability","Centrosome phenotype mechanism unresolved"]},{"year":2005,"claim":"Resolved how the BRC repeats interface with RAD51 filaments, showing non-equivalent repeats that bind distinct RAD51 surfaces and can either nucleate or disrupt filaments depending on stoichiometry.","evidence":"Electron microscopy of RAD51-DNA filaments with BRC peptides plus interaction mapping","pmids":["15937124"],"confidence":"Medium","gaps":["Used isolated BRC peptides rather than intact BRCA2","In vivo relevance of disruptive activity not established"]},{"year":2009,"claim":"Placed BRCA1 upstream of BRCA2 in the DNA-damage response by showing PALB2 bridges the two and is required for their concentration at damage sites and for HR.","evidence":"Reciprocal co-IP, siRNA depletion, laser-microirradiation focus recruitment, and HR reporter assay","pmids":["19268590"],"confidence":"High","gaps":["Did not define structural detail of the PALB2-BRCA2 contact","Quantitative contribution of this axis to overall recruitment unclear"]},{"year":2010,"claim":"Provided definitive biochemical proof of BRCA2's mediator activity by purifying full-length human BRCA2 and showing it loads RAD51 onto ssDNA, displaces RPA, and stabilizes filaments by blocking ATP hydrolysis.","evidence":"Reconstitution with full-length purified BRCA2; binding, competition, RPA-displacement, and ATPase assays","pmids":["20729832"],"confidence":"High","gaps":["Did not visualize nucleation kinetics at single-molecule resolution","Cellular regulation of this activity not addressed"]},{"year":2016,"claim":"Extended BRCA2 mediator function to meiosis by showing distinct BRC repeats prefer DMC1 and that full-length BRCA2 stimulates DMC1-mediated strand exchange.","evidence":"In vitro BRC-DMC1 binding and DMC1 strand-exchange assays with purified full-length BRCA2","pmids":["26976601"],"confidence":"High","gaps":["Meiosis-specific cofactors not yet identified at this stage","In vivo meiotic requirement of specific repeats untested"]},{"year":2017,"claim":"Distinguished BRCA2's HR function from fork protection and connected its loss to replication stress and metabolite-driven degradation, defining how partial BRCA2 loss drives instability.","evidence":"DNA fiber spreading and EM of replication intermediates with genetic perturbation; CRISPR conditional knockout in mammary cells; aldehyde-induced proteolysis assays with RNase H1 rescue","pmids":["29038466","28904335","28575672"],"confidence":"High","gaps":["Degradation machinery targeting BRCA2 not identified","Relative importance of HR vs fork protection may be context-dependent"]},{"year":2018,"claim":"Identified a non-canonical BRCA2 role in controlling R-loops at breaks by showing it recruits RNase H2 to DSBs in S/G2 phase.","evidence":"Co-IP, laser-microirradiation focus assay, and DRIP with cell-cycle staging","pmids":["30560944"],"confidence":"Medium","gaps":["Single lab without reciprocal structural validation","How R-loop control feeds into repair efficiency not quantified"]},{"year":2020,"claim":"Revealed regulatory layers governing BRCA2 — mitotic PLK1 phosphorylation building a PP2A-BUBR1 complex for chromosome alignment, DSS1/ssDNA control of oligomerization, and dedicated meiotic complexes.","evidence":"In vitro phosphorylation, co-IP, phosphopeptide NMR, chromosome alignment assays; pulldown and EM of oligomeric states; co-IP and mouse knockouts for MEILB2/BRME1 and HSF2BP","pmids":["32286328","32609828","32345962","31242413"],"confidence":"Medium","gaps":["Structural basis of full-length oligomerization unresolved","Crosstalk between mitotic and HR functions unclear"]},{"year":2021,"claim":"Connected damage signaling to RAD51 loading by showing ATM/ATR phosphorylation recruits PP2A-B56 to BRCA2 for efficient filament formation, with disruptive mutations conferring PARP-inhibitor sensitivity.","evidence":"Phosphoproteomics, reciprocal co-IP, HR assay, PARP inhibitor sensitivity, and motif mutagenesis","pmids":["34593815"],"confidence":"High","gaps":["Precise dephosphorylation substrate of recruited PP2A-B56 not defined","Temporal ordering relative to PALB2-mediated recruitment unclear"]},{"year":2024,"claim":"Demonstrated that a glycolytic metabolite can transiently inactivate BRCA2 by proteolysis, generating cancer-associated mutational signatures in monoallelic-mutant cells without biallelic loss.","evidence":"Protein stability assays, mutational signature analysis, patient-derived organoids, and mouse models with proteasome rescue","pmids":["38608703"],"confidence":"Medium","gaps":["Specific E3 ligase/proteolytic pathway not identified","In vivo frequency of this mechanism in tumorigenesis unquantified"]},{"year":null,"claim":"How the diverse BRCA2 regulatory inputs (PALB2/FANCD2 recruitment, ATM/ATR-PP2A signaling, PLK1 mitotic phosphorylation, oligomerization, and metabolite-driven degradation) are integrated in time and space to coordinate HR, fork protection, R-loop control, and mitotic fidelity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of full-length BRCA2 with its regulators","Mechanism switching between mitotic and meiotic functions undefined","Quantitative hierarchy of competing recruitment pathways unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[9,21]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9,13]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1,8,15]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[13,17,26]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14,7]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5,18,20]}],"complexes":["BRCA1-PALB2-BRCA2","BRCA2-PP2A-B56","BRCA2-MEILB2-BRME1","BRCA2-PLK1-PP2A-BUBR1"],"partners":["RAD51","DMC1","PALB2","DSS1","FANCD2","RNASEH2","HSF2BP","PLK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51587","full_name":"Breast cancer type 2 susceptibility protein","aliases":["Fanconi anemia group D1 protein"],"length_aa":3418,"mass_kda":384.2,"function":"Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. Part of a PALB2-scaffolded HR complex containing RAD51C and which is thought to play a role in DNA repair by HR. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity. In concert with NPM1, regulates centrosome duplication. Interacts with the TREX-2 complex (transcription and export complex 2) subunits PCID2 and SEM1, and is required to prevent R-loop-associated DNA damage and thus transcription-associated genomic instability. 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carriers.","date":"2017","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/28802188","citation_count":32,"is_preprint":false},{"pmid":"10807692","id":"PMC_10807692","title":"Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer.","date":"2000","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10807692","citation_count":32,"is_preprint":false},{"pmid":"35715464","id":"PMC_35715464","title":"ZFP281-BRCA2 prevents R-loop accumulation during DNA replication.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35715464","citation_count":31,"is_preprint":false},{"pmid":"36976771","id":"PMC_36976771","title":"BRCA2 chaperones RAD51 to single molecules of RPA-coated ssDNA.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36976771","citation_count":30,"is_preprint":false},{"pmid":"22666503","id":"PMC_22666503","title":"BRCA2 mutations and triple-negative breast cancer.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22666503","citation_count":30,"is_preprint":false},{"pmid":"9168997","id":"PMC_9168997","title":"Changes in BRCA2 expression during progression of the cell cycle.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9168997","citation_count":29,"is_preprint":false},{"pmid":"32609828","id":"PMC_32609828","title":"DSS1 and ssDNA regulate oligomerization of BRCA2.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32609828","citation_count":28,"is_preprint":false},{"pmid":"19737859","id":"PMC_19737859","title":"Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.","date":"2009","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/19737859","citation_count":28,"is_preprint":false},{"pmid":"18990703","id":"PMC_18990703","title":"Poly(ADP-ribose) polymerase-1 down-regulates BRCA2 expression through the BRCA2 promoter.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18990703","citation_count":28,"is_preprint":false},{"pmid":"18720553","id":"PMC_18720553","title":"Secondary BRCA1 and BRCA2 alterations and acquired chemoresistance.","date":"2008","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/18720553","citation_count":27,"is_preprint":false},{"pmid":"31413733","id":"PMC_31413733","title":"PALB2 (partner and localizer of BRCA2).","date":"2018","source":"Atlas of genetics and cytogenetics in oncology and haematology","url":"https://pubmed.ncbi.nlm.nih.gov/31413733","citation_count":27,"is_preprint":false},{"pmid":"36397405","id":"PMC_36397405","title":"BRCA2 gene mutation in cancer.","date":"2022","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36397405","citation_count":26,"is_preprint":false},{"pmid":"34687993","id":"PMC_34687993","title":"Genotype-cancer association in patients with Fanconi anemia due to pathogenic variants in FANCD1 (BRCA2) or FANCN (PALB2).","date":"2021","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34687993","citation_count":26,"is_preprint":false},{"pmid":"23411475","id":"PMC_23411475","title":"BRCA1 and BRCA2 mutations and female fertility.","date":"2013","source":"Current opinion in obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/23411475","citation_count":26,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40879,"output_tokens":6880,"usd":0.112919,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15989,"output_tokens":4697,"usd":0.098685,"stage2_stop_reason":"end_turn"},"total_usd":0.211604,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of a ~90 kDa BRCA2 C-terminal domain bound to DSS1 reveals three OB folds and a helix-turn-helix (HTH) motif; the domain binds single-stranded DNA (ssDNA) via the OB folds; the HTH motif is implicated in dsDNA binding; and this BRCA2 domain stimulates RAD51-mediated recombination in vitro.\",\n      \"method\": \"X-ray crystallography (3.1 Å apo structure; 3.5 Å ssDNA-bound structure), in vitro DNA-binding assays, in vitro RAD51 recombination stimulation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures at atomic resolution combined with biochemical recombination assay; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"12228710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Full-length purified human BRCA2 binds RAD51 and promotes assembly of RAD51 onto ssDNA over dsDNA, displaces RPA from ssDNA, and stabilizes RAD51-ssDNA filaments by blocking ATP hydrolysis; BRCA2 does not anneal RPA-coated ssDNA, indicating it does not function in ssDNA-annealing repair pathways.\",\n      \"method\": \"Purification of full-length human BRCA2, in vitro RAD51 binding, ssDNA/dsDNA competition assays, RPA displacement assay, ATPase assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with full-length purified protein, multiple orthogonal biochemical assays in one rigorous study\",\n      \"pmids\": [\"20729832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure and structure-guided mutagenesis reveal that the BRCA2 TR2 motif at the C-terminus binds across the protomer interface of the RAD51 nucleoprotein filament, acting as a molecular brace for adjacent RAD51 molecules and stabilizing the filament; TR2 targets an acidic-patch motif on human RAD51.\",\n      \"method\": \"Cryo-electron microscopy, structure-guided mutagenesis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure combined with mutagenesis validation in a single study\",\n      \"pmids\": [\"37919288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Single-molecule visualization shows that BRCA2 accelerates RAD51 nucleation on RPA-coated ssDNA to rates approaching association with naked ssDNA, overcoming the kinetic barrier imposed by RPA; a dimer of RAD51 is minimally required for spontaneous nucleation; BRCA2 can chaperone a preassembled short RAD51 filament onto RPA-coated ssDNA.\",\n      \"method\": \"Microfluidics, single-molecule fluorescence microscopy, micromanipulation of individual DNA molecules\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule reconstitution with full-length BRCA2, multiple quantitative measurements in one rigorous study\",\n      \"pmids\": [\"36976771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BRCA2 BRC repeats (BRC3 and BRC4) bind RAD51-DNA nucleoprotein filaments at low molar ratios, with BRC3 contacting the N-terminal domain of RAD51 and BRC4 contacting the nucleotide-binding core; at high concentrations the BRC repeats disrupt filaments. The eight BRC repeats are non-equivalent in their mode of RAD51 interaction.\",\n      \"method\": \"Electron microscopy of RAD51-DNA filaments incubated with BRC peptides, protein-protein interaction mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EM structural analysis with BRC repeat peptides, two orthogonal interaction-mapping approaches, single lab\",\n      \"pmids\": [\"15937124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRCA2 BRC repeats interact directly with the meiosis-specific recombinase DMC1; BRC1-3 bind RAD51 preferentially while BRC6-8 bind DMC1 preferentially; individual BRC repeats (except BRC4) stimulate DMC1-ssDNA complex formation; full-length BRCA2 stimulates DMC1-mediated DNA strand exchange between RPA-ssDNA and duplex DNA, identifying BRCA2 as a mediator of DMC1 recombination.\",\n      \"method\": \"In vitro BRC repeat-DMC1 binding assays, DNA strand exchange assay with purified full-length BRCA2, RPA-ssDNA competition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with full-length BRCA2, multiple biochemical assays demonstrating DMC1 mediator function\",\n      \"pmids\": [\"26976601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"BRCA2 is a ~460 kDa nuclear phosphoprotein that forms in vivo complexes with both p53 and RAD51; exogenous BRCA2 expression inhibits p53 transcriptional activity, and RAD51 co-expression enhances this inhibitory effect.\",\n      \"method\": \"Co-immunoprecipitation from human cells, transient transfection/transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and functional transcriptional assay, two orthogonal methods but single lab\",\n      \"pmids\": [\"9811893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Cells with a targeted truncation of murine Brca2 show proliferative impediment, G1 and G2/M arrest with elevated p53/p21, hypersensitivity to UV and MMS, spontaneous chromosomal breaks and aberrant chromatid exchanges, establishing Brca2 function in DNA repair.\",\n      \"method\": \"Mouse gene targeting (Brca2 truncation), colony survival assays, cell cycle analysis, cytogenetics\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts; foundational study replicated broadly\",\n      \"pmids\": [\"9660919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BRCA1 associates with BRCA2 through PALB2/FANCN; in PALB2-deficient cells the BRCA1-BRCA2 interaction is abrogated; BRCA1 promotes concentration of PALB2 and BRCA2 at DNA-damage sites; the BRCA1-PALB2 interaction is required for homologous recombination repair, placing BRCA1 upstream of BRCA2 in the DNA-damage response.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, laser-microirradiation focus recruitment assay, HR reporter assay\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, depletion rescue, functional HR assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"19268590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Monoubiquitination of FANCD2 (activated by DNA damage) is required for targeting FANCD2 to chromatin where it interacts with BRCA2 and promotes BRCA2 chromatin loading; the C-terminus of BRCA2 is required for functional colocalization of BRCA2 and FANCD2 in chromatin complexes.\",\n      \"method\": \"Chromatin fractionation, co-immunoprecipitation, immunofluorescence focus assays, complementation with wild-type BRCA2 cDNA in BRCA2-deficient cells\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin fractionation, co-IP, focus assays and functional complementation; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"15199141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FANCG directly binds BRCA2 at two separate sites flanking the BRC repeats (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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus confirmatory co-IP and co-localization, two orthogonal methods in one lab\",\n      \"pmids\": [\"12915460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EMSY protein binds BRCA2 within an exon 3-encoded region deleted in cancer, silences the transcriptional activation potential of BRCA2 exon 3, associates with chromatin regulators HP1β and BS69, and localizes to sites of DNA repair following DNA damage.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, transcriptional reporter assay, immunofluorescence\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding and functional silencing assays plus damage localization, single lab with multiple methods\",\n      \"pmids\": [\"14651845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"BRCA2 deficiency in XRCC11-complementation group hamster cells (V-C8) causes radioresistant DNA synthesis (checkpoint defect), extreme sensitivity to interstrand crosslinking agents, chromosomal instability, abnormal centrosomes, and reduced nuclear localization of RAD51.\",\n      \"method\": \"Chromosome 13 complementation, Brca2 cDNA complementation, clonogenic survival assays, cytogenetics, immunofluorescence for Rad51 localization\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation plus multiple cellular phenotype readouts establishing BRCA2/XRCC11 identity and RAD51 localization dependence\",\n      \"pmids\": [\"11756561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Reversed replication forks are entry points for nucleolytic fork degradation in BRCA2-defective cells; MRE11, PTIP, and RAD52 promote stalled fork degradation and chromosomal breakage in BRCA2-deficient cells; impairing fork reversal prevents fork degradation but increases chromosomal breakage; BRCA2 assembles stable RAD51 nucleofilaments on regressed arms to protect them from degradation.\",\n      \"method\": \"DNA fiber spreading, direct visualization of replication intermediates (electron microscopy), genetic inactivation of fork-reversal and degradation factors\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fiber spreading and EM imaging of replication intermediates, multiple genetic perturbations, clean mechanistic dissection in one study\",\n      \"pmids\": [\"29038466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLK1 phosphorylates BRCA2 at a conserved T207 site in mitosis, creating a PLK1 docking site; BRCA2 bound to PLK1 forms a complex with phosphatase PP2A and phosphorylated BUBR1; breast cancer variants S206C and T207A reduce BRCA2-PLK1 binding, destabilize this tetrameric complex, and cause unstable kinetochore-microtubule interactions, misaligned chromosomes, and aneuploidy.\",\n      \"method\": \"In vitro phosphorylation assay, co-immunoprecipitation, NMR structure of phosphopeptide, chromosomal alignment assays in cells expressing BRCA2 variants\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical phosphorylation, co-IP, structural characterization of phosphopeptide, and cellular phenotypic validation; multiple orthogonal methods\",\n      \"pmids\": [\"32286328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATM and ATR kinases phosphorylate a conserved region in BRCA2 in response to DSBs; these phosphorylations recruit the phosphatase PP2A-B56 to BRCA2 via a conserved binding motif; the BRCA2-PP2A-B56 complex is required for efficient RAD51 filament formation at DNA damage sites and HR-mediated repair; cancer-associated BRCA2 mutations that deregulate this interaction sensitize cells to PARP inhibition.\",\n      \"method\": \"Phosphoproteomics, co-immunoprecipitation, HR assay, PARP inhibitor sensitivity assay, mutagenesis of PP2A-binding motif\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, functional HR assay, drug sensitivity, and mutagenesis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"34593815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRCA2 directly interacts with RNase H2 and mediates RNase H2 localization to DSBs specifically in S/G2 phase, controlling DNA:RNA hybrid (R-loop) levels at DSBs; damage-induced lncRNAs contribute to recruitment of BRCA1, BRCA2, and RAD51 to DSBs without affecting DNA-end resection.\",\n      \"method\": \"Co-immunoprecipitation, laser-microirradiation and focus assay, DNA:RNA hybrid immunoprecipitation (DRIP), cell-cycle-staged analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional localization assay and DRIP, single lab with two orthogonal approaches\",\n      \"pmids\": [\"30560944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Formaldehyde selectively depletes BRCA2 via proteasomal degradation; heterozygous BRCA2 truncations sensitize cells to BRCA2 haploinsufficiency induced by formaldehyde or acetaldehyde, causing replication fork stalling, chromosomal aberrations, and R-loop accumulation; Ribonuclease H1 ameliorates these replication defects, linking BRCA2 inactivation to spontaneous mutagenesis via aberrant RNA-DNA hybrids.\",\n      \"method\": \"Western blot for BRCA2 protein levels after aldehyde treatment, proteasome inhibitor rescue, DNA fiber assay, cytogenetics, RNase H1 overexpression rescue\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteolysis assay, fiber analysis, genetic rescue) establishing mechanism in one study\",\n      \"pmids\": [\"28575672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HSF2BP interacts with a specific 68-amino acid region of BRCA2 (Gly2270–Thr2337, between BRC repeats and the DNA-binding domain) via armadillo repeats; this interaction is constitutive in mouse embryonic stem cells; Hsf2bp knockout mice are male infertile due to a severe HR defect during spermatogenesis.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid domain mapping, mouse knockout, meiotic HR assay\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP domain mapping, mouse knockout phenotype, single lab with two orthogonal methods\",\n      \"pmids\": [\"31242413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRCA2 forms a ternary complex with MEILB2 and BRME1 in meiosis; BRME1 stabilizes MEILB2 by preventing its self-association; BRCA2 binds the C-terminus of MEILB2; Brme1 knockout mice show defects in DSB repair, homolog synapsis, and crossover formation; ectopic expression of MEILB2-BRME1 in somatic cancer cells impairs mitotic HR.\",\n      \"method\": \"Co-immunoprecipitation, mouse knockout, immunofluorescence for DSB repair proteins, HR assay in somatic cells\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mouse KO phenotype, and functional HR assay; single lab with multiple methods\",\n      \"pmids\": [\"32345962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DSS1 and ssDNA counteract BRCA2 oligomerization; three self-interacting regions and two types of self-association (N-to-C and N-to-N terminal) were identified; the N-to-C interaction is sensitive to DSS1 and ssDNA, while the N-to-N interaction is modulated by ssDNA; defining a regulatory mechanism for BRCA2 oligomeric state.\",\n      \"method\": \"Biochemical pulldown assays, electron microscopic imaging of BRCA2 complexes, domain mapping\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical pulldown and EM imaging, single lab, two orthogonal methods\",\n      \"pmids\": [\"32609828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZFP281 interacts with BRCA2 and is required for BRCA2 recruitment to bivalent chromatin (with PRC2); depletion of ZFP281 or BRCA2 causes R-loop accumulation over bivalent regions and impairs DNA replication progression; ZFP281 cooperates with BRCA2 to prevent persistent R-loops at G/C-rich promoters.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), DRIP (DNA:RNA hybrid immunoprecipitation), DNA replication assay, siRNA depletion\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, DRIP, and functional replication assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35715464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The glycolytic metabolite methylglyoxal (MGO) triggers BRCA2 proteolysis, transiently disabling BRCA2 tumor suppressive functions in DNA repair and replication and causing functional haploinsufficiency; this generates a cancer-associated mutational signature (SBS) in non-malignant mammary cells without biallelic BRCA2 inactivation; BRCA2 monoallelic mutations predispose to these changes.\",\n      \"method\": \"Protein stability assays (western blot after MGO treatment), mutational signature analysis, patient-derived organoids, mouse models, proteasome inhibitor rescue\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteolysis assay, organoid and mouse model validation, mutational signature analysis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"38608703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PARP-1 binds a silencer region (-582 to -516) of the BRCA2 promoter in vitro and in vivo and down-regulates BRCA2 expression; PARP-1 inhibitors or PARP-1 siRNA increase endogenous BRCA2 expression; inhibition of PARP-1 activity reduces histone H3K9 acetylation and blocks PARP-1 binding to the BRCA2 promoter.\",\n      \"method\": \"Affinity purification and mass spectrometry, EMSA (gel shift), antibody super-shift, chromatin immunoprecipitation (ChIP), PARP-1 siRNA knockdown, PARP inhibitor treatment\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, EMSA, and functional knockdown experiments; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18990703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BRCA2 binds and stabilizes MAGE-D1 protein; BRCA2 and MAGE-D1 synergistically suppress cell proliferation independently of the p53 pathway; MAGE-D1 expression is required for BRCA2-mediated suppression of cell proliferation (shown by RNAi), establishing MAGE-D1 as a downstream effector of BRCA2 in growth suppression.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, cell proliferation assay, western blot\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP, RNAi epistasis, and proliferation assay; single lab with multiple methods\",\n      \"pmids\": [\"15930293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FANCC gene disruption in brca2ΔCTD (C-terminal domain truncation) cells reveals epistasis between FANCC and the BRCA2 CTD for X-ray sensitivity; however, combined fancc/brca2ΔCTD cells show additive sensitivity to cisplatin and increased MMC-induced chromosomal aberrations relative to either single mutant, indicating the FA pathway has a CTD-independent role in interstrand crosslink repair separate from BRCA2-RAD51-mediated HR.\",\n      \"method\": \"Conditional gene targeting (brca2ΔCTD), FANCC disruption, clonogenic survival assays, cytogenetics\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-mutant epistasis analysis with genetic complementation; single lab with well-defined genetic dissection\",\n      \"pmids\": [\"16687415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In non-transformed human mammary epithelial cells, BRCA2 loss causes replication stress associated with DNA under-replication, leading to mitotic abnormalities, 53BP1 nuclear body formation in the subsequent G1 phase, and G1 arrest; the HR function of BRCA2 (not stalled-fork protection) is primarily responsible for supporting cell viability in this context.\",\n      \"method\": \"CRISPR-Cas9 conditional BRCA2 knockout in human mammary epithelial cells, DNA fiber assay, immunofluorescence (53BP1 nuclear bodies, γH2AX), cell cycle analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple orthogonal readouts (fiber analysis, immunofluorescence, cell cycle) mechanistically dissecting HR vs. fork-protection functions\",\n      \"pmids\": [\"28904335\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRCA2 is a central mediator of homologous recombination (HR) that directly binds ssDNA through OB-fold domains and uses eight BRC repeats plus a C-terminal TR2 motif to load and stabilize RAD51 (and meiotic DMC1) nucleoprotein filaments on RPA-coated ssDNA, thereby driving error-free repair of DNA double-strand breaks; beyond HR, BRCA2 protects reversed replication forks from MRE11-mediated nucleolytic degradation via stable RAD51 filament assembly on regressed arms, controls DNA:RNA hybrid levels at DSBs by recruiting RNase H2, links BRCA1 to the HR machinery through the PALB2 scaffold, participates in mitotic chromosome alignment through a PLK1-T207 phosphorylation-dependent complex with PP2A-B56 and BUBR1, and its activity is regulated by ATM/ATR phosphorylation, PP2A-B56, DSS1-mediated monomerization, and PARP-1-mediated transcriptional repression—with loss of these functions leading to replication stress, chromosomal instability, and cancer predisposition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BRCA2 is a central mediator of homologous recombination (HR) that loads and stabilizes the RAD51 recombinase on resected DNA to drive error-free repair of double-strand breaks, with loss of function producing chromosomal instability, checkpoint defects, and crosslinker hypersensitivity [#7, #12]. A large C-terminal domain binds single-stranded DNA through three OB folds (with an HTH motif implicated in dsDNA binding) and stimulates RAD51-mediated recombination in vitro [#0]. Full-length BRCA2 binds RAD51 and selectively assembles it onto ssDNA over dsDNA, displaces RPA, and stabilizes the resulting filament by blocking RAD51 ATP hydrolysis [#1]; at the molecular level it accelerates RAD51 nucleation on RPA-coated ssDNA to rates approaching those on naked ssDNA, overcoming the kinetic barrier RPA imposes [#3]. The eight BRC repeats engage RAD51 non-equivalently to control filament assembly versus disruption [#4], while the C-terminal TR2 motif braces adjacent RAD51 protomers across the filament interface via an acidic-patch contact [#2]. BRCA2 is brought to damage sites through the BRCA1–PALB2 axis, which places BRCA1 upstream of BRCA2 in HR [#8], and through FANCD2/Fanconi-pathway interactions that promote its chromatin loading [#9, #10]. Beyond canonical HR, BRCA2 protects reversed replication forks from MRE11-, PTIP-, and RAD52-mediated nucleolytic degradation by assembling stable RAD51 filaments on regressed arms [#13], and it limits DNA:RNA hybrid (R-loop) accumulation at breaks and at G/C-rich chromatin by recruiting RNase H2 in S/G2 phase [#16, #21]. Its activity is governed by phosphoregulation and proteostasis: ATM/ATR phosphorylation recruits PP2A-B56 to promote RAD51 filament formation [#15], a PLK1-T207 phosphorylation event builds a PP2A–BUBR1 complex required for mitotic chromosome alignment [#14], DSS1 and ssDNA control BRCA2 oligomeric state [#20], and reactive metabolites such as formaldehyde and methylglyoxal trigger its proteasomal degradation to cause transient functional haploinsufficiency and mutagenesis [#17, #22]. BRCA2 additionally functions as a meiotic recombination mediator, stimulating DMC1 strand exchange through DMC1-preferring BRC repeats and acting within meiosis-specific complexes [#5, #18, #20].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that BRCA2 is a nuclear protein physically and functionally linked to the recombination and tumor-suppression machinery, by showing in vivo complexes with RAD51 and p53 and a DNA-repair phenotype upon disruption.\",\n      \"evidence\": \"Co-IP and transcriptional reporter assays in human cells; murine Brca2 truncation with survival, cell-cycle, and cytogenetic readouts\",\n      \"pmids\": [\"9811893\", \"9660919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical mechanism of RAD51 regulation\", \"p53 transcriptional effect not mapped to a direct molecular activity\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the structural basis of BRCA2 DNA engagement by resolving the DSS1-bound C-terminal domain with three OB folds that bind ssDNA and demonstrating it stimulates RAD51 recombination in vitro.\",\n      \"evidence\": \"X-ray crystallography (apo and ssDNA-bound) with in vitro DNA-binding and recombination assays\",\n      \"pmids\": [\"12228710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Used a domain fragment rather than full-length protein\", \"Did not show how RPA-coated ssDNA is handled in cells\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked BRCA2 deficiency directly to RAD51 nuclear localization and genome stability by identifying BRCA2 as the XRCC11 gene and characterizing crosslinker sensitivity, checkpoint defects, and centrosome abnormalities.\",\n      \"evidence\": \"Chromosome and cDNA complementation of V-C8 hamster cells with survival, cytogenetic, and RAD51 localization assays\",\n      \"pmids\": [\"11756561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate HR from fork-protection contributions to instability\", \"Centrosome phenotype mechanism unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved how the BRC repeats interface with RAD51 filaments, showing non-equivalent repeats that bind distinct RAD51 surfaces and can either nucleate or disrupt filaments depending on stoichiometry.\",\n      \"evidence\": \"Electron microscopy of RAD51-DNA filaments with BRC peptides plus interaction mapping\",\n      \"pmids\": [\"15937124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Used isolated BRC peptides rather than intact BRCA2\", \"In vivo relevance of disruptive activity not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed BRCA1 upstream of BRCA2 in the DNA-damage response by showing PALB2 bridges the two and is required for their concentration at damage sites and for HR.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA depletion, laser-microirradiation focus recruitment, and HR reporter assay\",\n      \"pmids\": [\"19268590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define structural detail of the PALB2-BRCA2 contact\", \"Quantitative contribution of this axis to overall recruitment unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided definitive biochemical proof of BRCA2's mediator activity by purifying full-length human BRCA2 and showing it loads RAD51 onto ssDNA, displaces RPA, and stabilizes filaments by blocking ATP hydrolysis.\",\n      \"evidence\": \"Reconstitution with full-length purified BRCA2; binding, competition, RPA-displacement, and ATPase assays\",\n      \"pmids\": [\"20729832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not visualize nucleation kinetics at single-molecule resolution\", \"Cellular regulation of this activity not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended BRCA2 mediator function to meiosis by showing distinct BRC repeats prefer DMC1 and that full-length BRCA2 stimulates DMC1-mediated strand exchange.\",\n      \"evidence\": \"In vitro BRC-DMC1 binding and DMC1 strand-exchange assays with purified full-length BRCA2\",\n      \"pmids\": [\"26976601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Meiosis-specific cofactors not yet identified at this stage\", \"In vivo meiotic requirement of specific repeats untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished BRCA2's HR function from fork protection and connected its loss to replication stress and metabolite-driven degradation, defining how partial BRCA2 loss drives instability.\",\n      \"evidence\": \"DNA fiber spreading and EM of replication intermediates with genetic perturbation; CRISPR conditional knockout in mammary cells; aldehyde-induced proteolysis assays with RNase H1 rescue\",\n      \"pmids\": [\"29038466\", \"28904335\", \"28575672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation machinery targeting BRCA2 not identified\", \"Relative importance of HR vs fork protection may be context-dependent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a non-canonical BRCA2 role in controlling R-loops at breaks by showing it recruits RNase H2 to DSBs in S/G2 phase.\",\n      \"evidence\": \"Co-IP, laser-microirradiation focus assay, and DRIP with cell-cycle staging\",\n      \"pmids\": [\"30560944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal structural validation\", \"How R-loop control feeds into repair efficiency not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed regulatory layers governing BRCA2 — mitotic PLK1 phosphorylation building a PP2A-BUBR1 complex for chromosome alignment, DSS1/ssDNA control of oligomerization, and dedicated meiotic complexes.\",\n      \"evidence\": \"In vitro phosphorylation, co-IP, phosphopeptide NMR, chromosome alignment assays; pulldown and EM of oligomeric states; co-IP and mouse knockouts for MEILB2/BRME1 and HSF2BP\",\n      \"pmids\": [\"32286328\", \"32609828\", \"32345962\", \"31242413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of full-length oligomerization unresolved\", \"Crosstalk between mitotic and HR functions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected damage signaling to RAD51 loading by showing ATM/ATR phosphorylation recruits PP2A-B56 to BRCA2 for efficient filament formation, with disruptive mutations conferring PARP-inhibitor sensitivity.\",\n      \"evidence\": \"Phosphoproteomics, reciprocal co-IP, HR assay, PARP inhibitor sensitivity, and motif mutagenesis\",\n      \"pmids\": [\"34593815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise dephosphorylation substrate of recruited PP2A-B56 not defined\", \"Temporal ordering relative to PALB2-mediated recruitment unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that a glycolytic metabolite can transiently inactivate BRCA2 by proteolysis, generating cancer-associated mutational signatures in monoallelic-mutant cells without biallelic loss.\",\n      \"evidence\": \"Protein stability assays, mutational signature analysis, patient-derived organoids, and mouse models with proteasome rescue\",\n      \"pmids\": [\"38608703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific E3 ligase/proteolytic pathway not identified\", \"In vivo frequency of this mechanism in tumorigenesis unquantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse BRCA2 regulatory inputs (PALB2/FANCD2 recruitment, ATM/ATR-PP2A signaling, PLK1 mitotic phosphorylation, oligomerization, and metabolite-driven degradation) are integrated in time and space to coordinate HR, fork protection, R-loop control, and mitotic fidelity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of full-length BRCA2 with its regulators\", \"Mechanism switching between mitotic and meiotic functions undefined\", \"Quantitative hierarchy of competing recruitment pathways unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [9, 21]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 8, 15]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [13, 17, 26]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14, 7]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5, 18, 20]}\n    ],\n    \"complexes\": [\n      \"BRCA1-PALB2-BRCA2\",\n      \"BRCA2-PP2A-B56\",\n      \"BRCA2-MEILB2-BRME1\",\n      \"BRCA2-PLK1-PP2A-BUBR1\"\n    ],\n    \"partners\": [\n      \"RAD51\",\n      \"DMC1\",\n      \"PALB2\",\n      \"DSS1\",\n      \"FANCD2\",\n      \"RNASEH2\",\n      \"HSF2BP\",\n      \"PLK1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}