BRCA2 (Breast cancer type 2 susceptibility protein) is a critical tumor suppressor that functions as a mediator of homologous recombination (HR) DNA repair. The protein contains multiple functional domains: BRC repeats that bind RAD51 recombinase, a DNA-binding domain (DBD) with OB folds and tower domain that binds ssDNA, and a C-terminal recombinase-binding region (CTRB) that engages both DNA and RAD51. BRCA2 loads and stabilizes RAD51 onto RPA-coated single-stranded DNA to form the presynaptic filament required for strand invasion during HR. Additionally, BRCA2 protects stalled and reversed replication forks from MRE11-mediated nucleolytic degradation, a function genetically separable from but coordinated with HR. Key partners include RAD51, PALB2, BRCA1-BARD1, and DSS1. Loss of BRCA2 function causes homologous recombination deficiency (HRD), conferring sensitivity to PARP inhibitors and platinum agents. Biallelic mutations cause Fanconi anemia (complementation group D1/FANCD1). BRCA2 localizes predominantly to the nucleus at DNA damage sites.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0003697
single-stranded DNA binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: BRCA2 binds single-stranded DNA through its DNA-binding domain (DBD) containing OB folds and through its C-terminal region (CTRB). This is essential for its function in loading RAD51 onto ssDNA during homologous recombination.
Reason: Core molecular function. The DBD with OB folds directly binds ssDNA to facilitate RAD51 loading. This is well-supported by structural and biochemical studies (PMID:20729832, Kwon et al. 2023 Nature Comm).
Supporting Evidence:
file:human/BRCA2/BRCA2-deep-research-falcon.md
The canonical DBD comprises a helical domain (HD), three OB folds (OB1-OB3), and a tower domain appendage. It binds DNA with high affinity and preferentially engages ssDNA in concert with DSS1
PMID:20729832
Purified human BRCA2 stimulates RAD51-mediated recombination
|
|
GO:0000724
double-strand break repair via homologous recombination
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: BRCA2 is the central mediator of homologous recombination repair, loading RAD51 onto resected ssDNA to form the presynaptic filament required for strand invasion.
Reason: Core biological process. BRCA2's primary function is mediating HR by facilitating RAD51 nucleoprotein filament formation. This is the defining function of BRCA2 and is well-established across multiple lines of evidence.
Supporting Evidence:
file:human/BRCA2/BRCA2-deep-research-falcon.md
BRCA2 is a genome maintenance factor that mediates homologous recombination (HR) by loading and stabilizing the recombinase RAD51 on resected single-stranded DNA (ssDNA) to form the presynaptic filament required for homology search and strand exchange
|
|
GO:0000724
double-strand break repair via homologous recombination
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Computational annotation consistent with BRCA2's established role in HR repair.
Reason: This IEA annotation is correctly capturing BRCA2's core function in HR repair. Redundant with IBA but valid.
|
|
GO:0003677
DNA binding
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: BRCA2 binds DNA through its DNA-binding domain containing OB folds. This is a parent term of ssDNA binding.
Reason: Valid but less specific than GO:0003697 (ssDNA binding). BRCA2 does bind DNA through its DBD and CTRB regions.
|
|
GO:0006281
DNA repair
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: BRCA2 functions in DNA repair, specifically homologous recombination repair.
Reason: Valid parent term of the more specific GO:0000724. BRCA2 is fundamentally a DNA repair protein.
|
|
GO:0005515
protein binding
|
IPI
PMID:10373512 Interaction between the product of the breast cancer suscept... |
REMOVE |
Summary: This paper describes the interaction between BRCA2 and DSS1 (SEM1), a functionally conserved protein. DSS1 binding is important for BRCA2 stability and function.
Reason: Generic protein binding is uninformative. The specific interaction (BRCA2-DSS1) is important but should be annotated with a more specific term if available.
Supporting Evidence:
PMID:10373512
Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals.
|
|
GO:0005515
protein binding
|
IPI
PMID:10551859 Expression of BRC repeats in breast cancer cells disrupts th... |
REMOVE |
Summary: Paper describes BRC repeats binding to RAD51 and disruption of this interaction leading to radiation hypersensitivity.
Reason: Generic protein binding is uninformative. The functionally relevant interaction is RAD51 binding via BRC repeats.
Supporting Evidence:
PMID:10551859
Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control.
|
|
GO:0005515
protein binding
|
IPI
PMID:12442171 Insights into DNA recombination from the structure of a RAD5... |
REMOVE |
Summary: Structural study of RAD51-BRCA2 complex revealing molecular basis of their interaction.
Reason: Generic protein binding is uninformative. This important structural work reveals RAD51 binding mechanism.
Supporting Evidence:
PMID:12442171
Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.
|
|
GO:0005515
protein binding
|
IPI
PMID:15115758 Direct interaction of FANCD2 with BRCA2 in DNA damage respon... |
REMOVE |
Summary: Paper describes direct interaction between FANCD2 and BRCA2 in DNA damage response.
Reason: Generic protein binding is uninformative. FANCD2 interaction is relevant to Fanconi anemia pathway.
Supporting Evidence:
PMID:15115758
Apr 28. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.
|
|
GO:0005515
protein binding
|
IPI
PMID:15800615 CDK-dependent phosphorylation of BRCA2 as a regulatory mecha... |
REMOVE |
Summary: CDK-dependent phosphorylation of BRCA2 regulates RAD51 binding and recombinational repair.
Reason: Generic protein binding is uninformative. The key finding is regulated RAD51 interaction.
Supporting Evidence:
PMID:15800615
CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair.
|
|
GO:0005515
protein binding
|
IPI
PMID:16205630 DSS1 is required for the stability of BRCA2. |
REMOVE |
Summary: DSS1 is required for BRCA2 stability.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:16205630
DSS1 is required for the stability of BRCA2.
|
|
GO:0005515
protein binding
|
IPI
PMID:17420451 Analysis of PALB2/FANCN-associated breast cancer families. |
REMOVE |
Summary: Analysis of PALB2/FANCN-associated breast cancer families, describing PALB2 interaction.
Reason: Generic protein binding is uninformative. PALB2 interaction is critical for BRCA2 function.
Supporting Evidence:
PMID:17420451
Analysis of PALB2/FANCN-associated breast cancer families.
|
|
GO:0005515
protein binding
|
IPI
PMID:17515903 Interaction with the BRCA2 C terminus protects RAD51-DNA fil... |
REMOVE |
Summary: Interaction with BRCA2 C terminus protects RAD51-DNA filaments from BRC repeat-mediated disassembly.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:17515903
Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats.
|
|
GO:0005515
protein binding
|
IPI
PMID:17515904 Stabilization of RAD51 nucleoprotein filaments by the C-term... |
REMOVE |
Summary: Stabilization of RAD51 nucleoprotein filaments by BRCA2 C-terminal region.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:17515904
May 21. Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2.
|
|
GO:0005515
protein binding
|
IPI
PMID:17541404 Interactions between human BRCA2 protein and the meiosis-spe... |
REMOVE |
Summary: Interactions between BRCA2 and meiosis-specific recombinase DMC1.
Reason: Generic protein binding is uninformative. DMC1 binding is relevant for meiotic recombination.
Supporting Evidence:
PMID:17541404
May 31. Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1.
|
|
GO:0005515
protein binding
|
IPI
PMID:18212739 FANCG promotes formation of a newly identified protein compl... |
REMOVE |
Summary: FANCG promotes formation of complex containing BRCA2, FANCD2 and XRCC3.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:18212739
Jan 21. FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3.
|
|
GO:0005515
protein binding
|
IPI
PMID:18264088 Resistance to therapy caused by intragenic deletion in BRCA2... |
REMOVE |
Summary: Resistance to therapy caused by intragenic deletion in BRCA2.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:18264088
Resistance to therapy caused by intragenic deletion in BRCA2.
|
|
GO:0005515
protein binding
|
IPI
PMID:19303847 The BRC repeats of BRCA2 modulate the DNA-binding selectivit... |
REMOVE |
Summary: BRC repeats modulate DNA-binding selectivity of RAD51.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:19303847
The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51.
|
|
GO:0005515
protein binding
|
IPI
PMID:19369211 PALB2 is an integral component of the BRCA complex required ... |
REMOVE |
Summary: PALB2 is integral component of BRCA complex required for HR repair. With BRCA1 and PALB2.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:19369211
PALB2 is an integral component of the BRCA complex required for homologous recombination repair.
|
|
GO:0005515
protein binding
|
IPI
PMID:19609323 Structural basis for recruitment of BRCA2 by PALB2. |
REMOVE |
Summary: Structural basis for BRCA2 recruitment by PALB2.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:19609323
Structural basis for recruitment of BRCA2 by PALB2.
|
|
GO:0005515
protein binding
|
IPI
PMID:19628690 The BRC repeats of human BRCA2 differentially regulate RAD51... |
REMOVE |
Summary: BRC repeats differentially regulate RAD51 binding on ssDNA vs dsDNA.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:19628690
The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange.
|
|
GO:0005515
protein binding
|
IPI
PMID:20421506 Mapping the physical and functional interactions between the... |
REMOVE |
Summary: Physical and functional interactions between p53 and BRCA2.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:20421506
Mapping the physical and functional interactions between the tumor suppressors p53 and BRCA2.
|
|
GO:0005515
protein binding
|
IPI
PMID:20729832 Purified human BRCA2 stimulates RAD51-mediated recombination... |
REMOVE |
Summary: Purified BRCA2 stimulates RAD51-mediated recombination. Key mechanistic study.
Reason: Generic protein binding is uninformative. The important finding is RAD51 regulation.
Supporting Evidence:
PMID:20729832
Purified human BRCA2 stimulates RAD51-mediated recombination.
|
|
GO:0005515
protein binding
|
IPI
PMID:20729859 Human BRCA2 protein promotes RAD51 filament formation on RPA... |
REMOVE |
Summary: BRCA2 promotes RAD51 filament formation on RPA-covered ssDNA.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:20729859
Aug 22. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA.
|
|
GO:0005515
protein binding
|
IPI
PMID:21399666 A mitotic function for the high-mobility group protein HMG20... |
REMOVE |
Summary: HMG20b interaction with BRC repeats of BRCA2 has mitotic function.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:21399666
A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor.
|
|
GO:0005515
protein binding
|
IPI
PMID:21601571 Valine 1532 of human BRC repeat 4 plays an important role in... |
REMOVE |
Summary: Valine 1532 of BRC repeat 4 important for BRCA2-RAD51 interaction.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:21601571
Epub 2011 May 17. Valine 1532 of human BRC repeat 4 plays an important role in the interaction between BRCA2 and RAD51.
|
|
GO:0005515
protein binding
|
IPI
PMID:22116401 Synaptonemal complex protein SYCP3 impairs mitotic recombina... |
REMOVE |
Summary: Synaptonemal complex protein SYCP3 impairs mitotic recombination by interfering with BRCA2.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:22116401
Synaptonemal complex protein SYCP3 impairs mitotic recombination by interfering with BRCA2.
|
|
GO:0005515
protein binding
|
IPI
PMID:22193777 ChAM, a novel motif that mediates PALB2 intrinsic chromatin ... |
REMOVE |
Summary: ChAM motif mediates PALB2 chromatin binding and facilitates DNA repair.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:22193777
ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair.
|
|
GO:0005515
protein binding
|
IPI
PMID:22293751 APRIN is a cell cycle specific BRCA2-interacting protein req... |
REMOVE |
Summary: APRIN is cell cycle specific BRCA2-interacting protein required for genome integrity.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:22293751
APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer.
|
|
GO:0005515
protein binding
|
IPI
PMID:24013206 A cancer-associated BRCA2 mutation reveals masked nuclear ex... |
REMOVE |
Summary: Cancer-associated BRCA2 mutation reveals masked nuclear export signals.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:24013206
Sep 8. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization.
|
|
GO:0005515
protein binding
|
IPI
PMID:24141787 Breast cancer-associated missense mutants of the PALB2 WD40 ... |
REMOVE |
Summary: PALB2 WD40 domain directly binds RAD51C, RAD51 and BRCA2.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:24141787
Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
|
|
GO:0005515
protein binding
|
IPI
PMID:24485656 Breast cancer proteins PALB2 and BRCA2 stimulate polymerase ... |
REMOVE |
Summary: PALB2 and BRCA2 stimulate polymerase eta at blocked replication forks.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:24485656
2014 Jan 30. Breast cancer proteins PALB2 and BRCA2 stimulate polymerase η in recombination-associated DNA synthesis at blocked replication forks.
|
|
GO:0005515
protein binding
|
IPI
PMID:24981860 Human-chromatin-related protein interactions identify a deme... |
REMOVE |
Summary: Human chromatin-related protein interactions.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:24981860
2014 Jun 26. Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
|
|
GO:0005515
protein binding
|
IPI
PMID:25282148 Structure and mechanism of action of the BRCA2 breast cancer... |
REMOVE |
Summary: Structure and mechanism of action of BRCA2 breast cancer tumor suppressor.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:25282148
2014 Oct 5. Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor.
|
|
GO:0005515
protein binding
|
IPI
PMID:28319063 Compromised BRCA1-PALB2 interaction is associated with breas... |
REMOVE |
Summary: Compromised BRCA1-PALB2 interaction associated with breast cancer risk.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:28319063
Mar 20. Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.
|
|
GO:0005515
protein binding
|
IPI
PMID:30410870 Two Missense Variants Detected in Breast Cancer Probands Pre... |
REMOVE |
Summary: Two missense variants preventing BRCA2-PALB2 interaction.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:30410870
Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2 Protein Interaction.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
REMOVE |
Summary: Dual proteome-scale networks reveal cell-specific remodeling of human interactome.
Reason: Generic protein binding is uninformative. High-throughput study.
Supporting Evidence:
PMID:33961781
2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:34591612 A protein interaction landscape of breast cancer. |
REMOVE |
Summary: Protein interaction landscape of breast cancer.
Reason: Generic protein binding is uninformative. High-throughput study.
Supporting Evidence:
PMID:34591612
Oct 1. A protein interaction landscape of breast cancer.
|
|
GO:0005515
protein binding
|
IPI
PMID:39009827 Proteome-scale characterisation of motif-based interactome r... |
REMOVE |
Summary: Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:39009827
2024 Jul 15. Proteome-scale characterisation of motif-based interactome rewiring by disease mutations.
|
|
GO:0005515
protein binding
|
IPI
PMID:9560268 The BRC repeats in BRCA2 are critical for RAD51 binding and ... |
REMOVE |
Summary: BRC repeats critical for RAD51 binding and resistance to methyl methanesulfonate.
Reason: Generic protein binding is uninformative. The important finding is RAD51 binding via BRC repeats.
Supporting Evidence:
PMID:9560268
The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:21601571 Valine 1532 of human BRC repeat 4 plays an important role in... |
KEEP AS NON CORE |
Summary: BRCA2 can form homodimers or oligomers.
Reason: BRCA2 oligomerization has been reported but is not central to its primary function in HR repair.
Supporting Evidence:
PMID:21601571
Epub 2011 May 17. Valine 1532 of human BRC repeat 4 plays an important role in the interaction between BRCA2 and RAD51.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:25282148 Structure and mechanism of action of the BRCA2 breast cancer... |
KEEP AS NON CORE |
Summary: BRCA2 homodimerization.
Reason: Oligomerization is a secondary property, not core function.
Supporting Evidence:
PMID:25282148
2014 Oct 5. Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor.
|
|
GO:0000722
telomere maintenance via recombination
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 has been shown to localize to telomeres and facilitate telomere replication and capping through RAD51 loading (PMID:21076401).
Reason: BRCA2 does function at telomeres via its general HR function, but this is not the primary cellular role. Supported by PMID:21076401.
|
|
GO:0001556
oocyte maturation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Developmental process in which oocytes develop. BRCA2 is required for proper meiotic recombination.
Reason: Downstream developmental consequence of BRCA2's role in meiotic HR. Not a direct molecular function.
|
|
GO:0001833
inner cell mass cell proliferation
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Embryonic developmental process. BRCA2 knockout is embryonic lethal.
Reason: This is a distal phenotypic consequence of loss of genome maintenance, not a specific function of BRCA2.
|
|
GO:0006302
double-strand break repair
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Parent term of HR repair. BRCA2 specifically functions in HR, not NHEJ.
Reason: Valid parent term. BRCA2 functions specifically in the HR subtype of DSB repair.
|
|
GO:0007283
spermatogenesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 is required for meiotic recombination during spermatogenesis. HSF2BP interaction is required for spermatogenesis (PMID:31242413).
Reason: BRCA2 is essential for meiosis, and loss causes infertility. This is a consequence of its meiotic HR function.
|
|
GO:0007420
brain development
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: BRCA2 loss leads to developmental defects including in brain. This is pleiotropic.
Reason: Distal phenotypic effect of genome instability, not a specific BRCA2 function.
|
|
GO:0008283
cell population proliferation
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Generic cell proliferation term.
Reason: Too generic. BRCA2 loss affects proliferation due to genome instability, not via direct regulation of proliferation.
|
|
GO:0008585
female gonad development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 required for meiosis which is essential for gonad development.
Reason: Downstream consequence of meiotic HR function.
|
|
GO:0008630
intrinsic apoptotic signaling pathway in response to DNA damage
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: BRCA2 loss leads to activation of apoptosis due to unrepaired DNA damage.
Reason: BRCA2 does not directly regulate apoptosis. Apoptosis is a downstream consequence of HR deficiency.
|
|
GO:0010165
response to X-ray
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2-deficient cells are hypersensitive to X-rays due to defective HR repair.
Reason: Valid but represents the phenotypic response rather than BRCA2's direct function.
|
|
GO:0010225
response to UV-C
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Response to UV damage.
Reason: Phenotypic response to DNA damage. BRCA2 participates in repair of UV-induced lesions via HR.
|
|
GO:0010332
response to gamma radiation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 is essential for repair of gamma-radiation induced DSBs.
Reason: Phenotypic response. BRCA2 repairs radiation-induced DSBs via HR.
|
|
GO:0030097
hemopoiesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Biallelic BRCA2 mutations cause Fanconi anemia with bone marrow failure.
Reason: Downstream phenotype of BRCA2/FANCD1 deficiency. Not a direct function.
|
|
GO:0030330
DNA damage response, signal transduction by p53 class mediator
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: p53 activation occurs when BRCA2-mediated repair fails.
Reason: BRCA2 does not directly regulate p53 signaling. This is an indirect consequence.
|
|
GO:0031297
replication fork processing
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: BRCA2 protects stalled and reversed replication forks from nucleolytic degradation by MRE11.
Reason: Core function. BRCA2 stabilizes RAD51 on reversed forks to prevent degradation. This is mechanistically separable from but related to HR function.
Supporting Evidence:
file:human/BRCA2/BRCA2-deep-research-falcon.md
Beyond DSB repair, BRCA2 stabilizes RAD51 on stalled/reversed replication forks to prevent nucleolytic degradation (e.g., by MRE11) and to promote restart, a function genetically and biochemically separable but coordinated with HR
|
|
GO:0032465
regulation of cytokinesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 has been implicated in centrosome and cytokinesis regulation.
Reason: BRCA2 localizes to centrosomes and affects mitotic fidelity, but this is secondary to HR function.
|
|
GO:0042771
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Apoptosis induction when BRCA2-mediated repair fails.
Reason: Indirect consequence of HR deficiency, not a direct BRCA2 function.
|
|
GO:0043009
chordate embryonic development
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: BRCA2 knockout is embryonic lethal.
Reason: Distal phenotypic effect of genome instability.
|
|
GO:0045931
positive regulation of mitotic cell cycle
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: BRCA2 loss causes cell cycle arrest.
Reason: BRCA2 does not directly regulate cell cycle. Cell cycle effects are consequence of checkpoint activation.
|
|
GO:0051276
chromosome organization
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 affects chromosome stability through HR repair.
Reason: Valid but vague. BRCA2 contributes to chromosome stability via its repair function.
|
|
GO:0071425
hematopoietic stem cell proliferation
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: BRCA2/FANCD1 deficiency causes bone marrow failure.
Reason: Phenotypic consequence of Fanconi anemia, not direct function.
|
|
GO:0072089
stem cell proliferation
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Generic stem cell term.
Reason: Too generic and represents phenotypic consequence.
|
|
GO:0090398
cellular senescence
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: BRCA2 loss can trigger senescence.
Reason: Senescence is a downstream response to DNA damage, not a BRCA2 function.
|
|
GO:0000724
double-strand break repair via homologous recombination
|
IDA
PMID:28398198 Functional and mutational landscapes of BRCA1 for homology-d... |
ACCEPT |
Summary: Functional and mutational landscapes of BRCA1 for HR and therapy resistance.
Reason: Direct experimental evidence for BRCA2's role in HR repair.
Supporting Evidence:
PMID:28398198
Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance.
|
|
GO:0005515
protein binding
|
IPI
PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo... |
REMOVE |
Summary: Non-catalytic roles for XPG with BRCA1 and BRCA2 in HR and genome stability.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:26833090
2016 Jan 28. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.
|
|
GO:0005515
protein binding
|
IPI
PMID:31242413 HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Req... |
REMOVE |
Summary: HSF2BP interacts with conserved domain of BRCA2 for spermatogenesis.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:31242413
HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse Spermatogenesis.
|
|
GO:0005515
protein binding
|
IDA
PMID:9774970 Stable interaction between the products of the BRCA1 and BRC... |
REMOVE |
Summary: Stable interaction between BRCA1 and BRCA2 in mitotic and meiotic cells.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:9774970
Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.
|
|
GO:0000724
double-strand break repair via homologous recombination
|
IMP
PMID:21719596 A comprehensive functional characterization of BRCA2 variant... |
ACCEPT |
Summary: Comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia.
Reason: Mutant phenotype analysis confirms BRCA2's role in HR.
Supporting Evidence:
PMID:21719596
Jun 30. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay.
|
|
GO:0005515
protein binding
|
IPI
PMID:21719596 A comprehensive functional characterization of BRCA2 variant... |
REMOVE |
Summary: BRCA2 variants characterized for functional interactions.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:21719596
Jun 30. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay.
|
|
GO:0005515
protein binding
|
IPI
PMID:25585578 FBH1 influences DNA replication fork stability and homologou... |
REMOVE |
Summary: FBH1 influences DNA replication fork stability through RAD51 ubiquitylation.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:25585578
FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51.
|
|
GO:0010484
histone H3 acetyltransferase activity
|
IDA
PMID:9619837 The BRCA2 is a histone acetyltransferase. |
UNDECIDED |
Summary: Original 1998 paper claimed BRCA2 has intrinsic HAT activity. However, this finding is controversial and has not been widely replicated. A 1998 study (PMID:9824164) showed that BRCA2 associates with acetyltransferase activity when bound to P/CAF, suggesting the HAT activity is from associated P/CAF, not intrinsic to BRCA2.
Reason: The claim of intrinsic HAT activity is contested. PMID:9824164 indicates the activity comes from P/CAF association. This needs expert review.
Supporting Evidence:
PMID:9619837
The BRCA2 is a histone acetyltransferase.
|
|
GO:0010485
histone H4 acetyltransferase activity
|
IDA
PMID:9619837 The BRCA2 is a histone acetyltransferase. |
UNDECIDED |
Summary: Same controversial claim as H3 HAT activity.
Reason: Intrinsic HAT activity claim is contested. Needs expert review.
Supporting Evidence:
PMID:9619837
The BRCA2 is a histone acetyltransferase.
|
|
GO:0005515
protein binding
|
IPI
PMID:19423707 PALB2 regulates recombinational repair through chromatin ass... |
REMOVE |
Summary: PALB2 regulates recombinational repair through chromatin association and oligomerization.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:19423707
2009 May 7. PALB2 regulates recombinational repair through chromatin association and oligomerization.
|
|
GO:0000724
double-strand break repair via homologous recombination
|
IDA
PMID:20729832 Purified human BRCA2 stimulates RAD51-mediated recombination... |
ACCEPT |
Summary: Purified human BRCA2 stimulates RAD51-mediated recombination. Key biochemical study demonstrating BRCA2's direct role in HR.
Reason: High-quality direct assay evidence confirming BRCA2's role in stimulating RAD51-dependent recombination.
Supporting Evidence:
PMID:20729832
Purified human BRCA2 stimulates RAD51-mediated recombination.
|
|
GO:0003697
single-stranded DNA binding
|
IDA
PMID:20729832 Purified human BRCA2 stimulates RAD51-mediated recombination... |
ACCEPT |
Summary: Biochemical demonstration that purified BRCA2 binds ssDNA directly.
Reason: Direct biochemical evidence for ssDNA binding activity.
Supporting Evidence:
PMID:20729832
Purified human BRCA2 stimulates RAD51-mediated recombination.
|
|
GO:0002020
protease binding
|
IPI
PMID:15314155 BRCA2 is ubiquitinated in vivo and interacts with USP11, a d... |
KEEP AS NON CORE |
Summary: BRCA2 interacts with USP11, a deubiquitinating enzyme.
Reason: USP11 is a DUB that regulates BRCA2 stability. This is a regulatory interaction, not core function.
Supporting Evidence:
PMID:15314155
BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage.
|
|
GO:0005515
protein binding
|
IPI
PMID:12242698 Highlight: BRCA1 and BRCA2 proteins in breast cancer. |
REMOVE |
Summary: BRCA1 and BRCA2 proteins in breast cancer.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:12242698
Highlight: BRCA1 and BRCA2 proteins in breast cancer.
|
|
GO:0005515
protein binding
|
IPI
PMID:15967112 WDRPUH, a novel WD-repeat-containing protein, is highly expr... |
REMOVE |
Summary: WDRPUH interaction with BRCA2.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:15967112
WDRPUH, a novel WD-repeat-containing protein, is highly expressed in human hepatocellular carcinoma and involved in cell proliferation.
|
|
GO:0005515
protein binding
|
IPI
PMID:11597317 BRCA2 and homologous recombination. |
REMOVE |
Summary: BRCA2 and homologous recombination review.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:11597317
BRCA2 and homologous recombination.
|
|
GO:0005515
protein binding
|
IPI
PMID:15930293 BRCA2 suppresses cell proliferation via stabilizing MAGE-D1. |
REMOVE |
Summary: BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:15930293
BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
|
|
GO:0005515
protein binding
|
IPI
PMID:16099937 Analysis of albumin-associated peptides and proteins from ov... |
REMOVE |
Summary: Analysis of albumin-associated peptides from ovarian cancer patients.
Reason: Generic protein binding is uninformative. Low relevance study.
Supporting Evidence:
PMID:16099937
2005 Aug 11. Analysis of albumin-associated peptides and proteins from ovarian cancer patients.
|
|
GO:0005515
protein binding
|
IPI
PMID:16275750 Centrobin: a novel daughter centriole-associated protein tha... |
REMOVE |
Summary: Centrobin centriole duplication study.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:16275750
Centrobin: a novel daughter centriole-associated protein that is required for centriole duplication.
|
|
GO:0005515
protein binding
|
IPI
PMID:9774970 Stable interaction between the products of the BRCA1 and BRC... |
REMOVE |
Summary: BRCA1-BRCA2 interaction in mitotic and meiotic cells.
Reason: Generic protein binding is uninformative.
Supporting Evidence:
PMID:9774970
Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.
|
|
GO:0043015
gamma-tubulin binding
|
IPI
PMID:17286961 Interference with BRCA2, which localizes to the centrosome d... |
KEEP AS NON CORE |
Summary: BRCA2 localizes to centrosome and interacts with gamma-tubulin. Interference leads to abnormal nuclear division.
Reason: BRCA2 does localize to centrosomes and binds gamma-tubulin, but this is secondary to its HR function.
Supporting Evidence:
PMID:17286961
Interference with BRCA2, which localizes to the centrosome during S and early M phase, leads to abnormal nuclear division.
|
|
GO:0004402
histone acetyltransferase activity
|
IDA
NOT
PMID:9824164 BRCA2 associates with acetyltransferase activity when bound ... |
REMOVE |
Summary: BRCA2 associates with acetyltransferase activity when bound to P/CAF. This study shows HAT activity comes from P/CAF, not BRCA2 itself.
Reason: This annotation has a NOT qualifier in the GOA file, meaning BRCA2 does NOT have intrinsic HAT activity. The activity comes from associated P/CAF.
Supporting Evidence:
PMID:9824164
BRCA2 associates with acetyltransferase activity when bound to P/CAF.
|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: BRCA2 is predominantly nuclear where it functions in DNA repair.
Reason: Core localization. BRCA2 must be nuclear to perform its DNA repair function.
|
|
GO:0006355
regulation of DNA-templated transcription
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: BRCA2 has been reported to have transcriptional activation activity in its N-terminal domain.
Reason: BRCA2 contains a transcriptional activation domain and has been shown to activate transcription (PMID:9126734), but this is not its primary function.
|
|
GO:0006338
chromatin remodeling
|
IEA
GO_REF:0000108 |
UNDECIDED |
Summary: Inferred from claimed HAT activity.
Reason: This inference depends on the contested HAT activity claim. Needs expert review.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Nuclear localization.
Reason: Consistent with known nuclear function.
|
|
GO:0005813
centrosome
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: BRCA2 localizes to centrosomes during S and early M phase.
Reason: BRCA2 does localize to centrosomes (PMID:17286961, PMID:21276791) but this is secondary to its nuclear DNA repair function.
|
|
GO:0006310
DNA recombination
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Parent term of HR.
Reason: Valid. BRCA2 is a key recombination mediator.
|
|
GO:0006974
DNA damage response
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: BRCA2 is part of the DNA damage response.
Reason: BRCA2 is recruited to and functions at DNA damage sites.
|
|
GO:0000152
nuclear ubiquitin ligase complex
|
IDA
PMID:14636569 Regulation of BRCC, a holoenzyme complex containing BRCA1 an... |
ACCEPT |
Summary: BRCA2 is part of the BRCC holoenzyme complex which contains BRCA1 and has ubiquitin ligase activity.
Reason: BRCA2 is part of multi-protein DNA repair complexes with ubiquitin ligase activity.
Supporting Evidence:
PMID:14636569
Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.
|
|
GO:0005634
nucleus
|
IDA
PMID:14636569 Regulation of BRCC, a holoenzyme complex containing BRCA1 an... |
ACCEPT |
Summary: Nuclear localization is essential for BRCA2's role in homologous recombination DNA repair.
Reason: Nuclear localization is core to BRCA2 function in DNA repair, directly demonstrated by IDA evidence.
Supporting Evidence:
file:human/BRCA2/BRCA2-deep-research-falcon.md
BRCA2 is predominantly nuclear and accumulates at DNA double-strand breaks, ssDNA gaps, and stressed/reversed replication forks
PMID:14636569
Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.
|
|
GO:0071479
cellular response to ionizing radiation
|
IMP
PMID:14636569 Regulation of BRCC, a holoenzyme complex containing BRCA1 an... |
ACCEPT |
Summary: BRCA2 is required for proper response to ionizing radiation.
Reason: BRCA2 is essential for repair of radiation-induced DSBs via HR.
Supporting Evidence:
PMID:14636569
Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.
|
|
GO:2000001
regulation of DNA damage checkpoint
|
NAS
PMID:14636569 Regulation of BRCC, a holoenzyme complex containing BRCA1 an... |
KEEP AS NON CORE |
Summary: BRCA2 participates in checkpoint regulation.
Reason: BRCA2 affects checkpoint signaling but is not a direct checkpoint regulator.
Supporting Evidence:
PMID:14636569
Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.
|
|
GO:0005694
chromosome
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: BRCA2 associates with chromosomes at DNA damage sites.
Reason: BRCA2 is recruited to chromosomal DNA damage sites.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Some BRCA2 is cytoplasmic before nuclear import.
Reason: BRCA2 is predominantly nuclear but some cytoplasmic localization exists.
|
|
GO:0007141
male meiosis I
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 is required for meiotic recombination.
Reason: BRCA2 functions in meiotic HR, essential for meiosis I.
|
|
GO:0070200
establishment of protein localization to telomere
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: BRCA2 facilitates RAD51 localization to telomeres.
Reason: BRCA2 loads RAD51 at telomeres for replication (PMID:21076401).
|
|
GO:0005634
nucleus
|
NAS
PMID:19369211 PALB2 is an integral component of the BRCA complex required ... |
ACCEPT |
Summary: Nuclear localization in BRCA complex.
Reason: Consistent with established nuclear function.
Supporting Evidence:
PMID:19369211
PALB2 is an integral component of the BRCA complex required for homologous recombination repair.
|
|
GO:1990391
DNA repair complex
|
IPI
PMID:19369211 PALB2 is an integral component of the BRCA complex required ... |
ACCEPT |
Summary: BRCA2 is part of the BRCA complex with BRCA1 and PALB2 required for HR repair.
Reason: Core component of DNA repair complex.
Supporting Evidence:
PMID:19369211
PALB2 is an integral component of the BRCA complex required for homologous recombination repair.
|
|
GO:0005654
nucleoplasm
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: BRCA2 localizes to the nucleoplasm where it participates in DNA repair processes.
Reason: Nucleoplasm localization is consistent with BRCA2's role in nuclear DNA repair machinery.
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
KEEP AS NON CORE |
Summary: Some BRCA2 is present in cytosol.
Reason: BRCA2 is predominantly nuclear; cytosolic localization is secondary.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9763200 |
KEEP AS NON CORE |
Summary: Reactome pathway annotation for cytosolic BRCA2.
Reason: Secondary localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9709571 |
ACCEPT |
Summary: Reactome pathway annotation.
Reason: Consistent with nuclear function.
|
|
GO:0005634
nucleus
|
IDA
PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo... |
ACCEPT |
Summary: Nuclear localization with XPG in HR complex.
Reason: Consistent with nuclear DNA repair function.
Supporting Evidence:
PMID:26833090
2016 Jan 28. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.
|
|
GO:0032991
protein-containing complex
|
IDA
PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo... |
ACCEPT |
Summary: BRCA2 is part of HR protein complex.
Reason: BRCA2 functions in multi-protein complexes.
Supporting Evidence:
PMID:26833090
2016 Jan 28. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9709601 |
ACCEPT |
Summary: Reactome pathway annotation.
Reason: Nucleoplasm localization.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9709268 |
KEEP AS NON CORE |
Summary: Reactome pathway annotation.
Reason: Secondary localization.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9709273 |
KEEP AS NON CORE |
Summary: Reactome pathway annotation.
Reason: Secondary localization.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9763137 |
KEEP AS NON CORE |
Summary: Reactome pathway - BRCA2 binds SEM1(DSS1).
Reason: Secondary localization.
|
|
GO:0032991
protein-containing complex
|
IDA
PMID:9774970 Stable interaction between the products of the BRCA1 and BRC... |
ACCEPT |
Summary: BRCA1-BRCA2 complex in mitotic and meiotic cells.
Reason: BRCA2 forms complexes with BRCA1 and other HR proteins.
Supporting Evidence:
PMID:9774970
Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.
|
|
GO:0000800
lateral element
|
IDA
PMID:9774970 Stable interaction between the products of the BRCA1 and BRC... |
KEEP AS NON CORE |
Summary: BRCA2 localizes to synaptonemal complex lateral elements during meiosis.
Reason: Meiosis-specific localization for meiotic HR function.
Supporting Evidence:
PMID:9774970
Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.
|
|
GO:0000781
chromosome, telomeric region
|
IDA
PMID:21076401 BRCA2 acts as a RAD51 loader to facilitate telomere replicat... |
KEEP AS NON CORE |
Summary: BRCA2 acts as RAD51 loader at telomeres for telomere replication and capping.
Reason: Telomeric localization for HR-dependent telomere maintenance.
Supporting Evidence:
PMID:21076401
Nov 14. BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping.
|
|
GO:0070200
establishment of protein localization to telomere
|
IDA
PMID:21076401 BRCA2 acts as a RAD51 loader to facilitate telomere replicat... |
KEEP AS NON CORE |
Summary: BRCA2 localizes RAD51 to telomeres.
Reason: Extension of BRCA2's RAD51 loading function to telomeres.
Supporting Evidence:
PMID:21076401
Nov 14. BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping.
|
|
GO:1990426
mitotic recombination-dependent replication fork processing
|
IMP
PMID:21076401 BRCA2 acts as a RAD51 loader to facilitate telomere replicat... |
ACCEPT |
Summary: BRCA2 required for recombination-dependent fork processing at telomeres.
Reason: Core function - BRCA2's role in replication fork processing is well-established.
Supporting Evidence:
PMID:21076401
Nov 14. BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5685242 |
ACCEPT |
Summary: Reactome - CHEK1 phosphorylates BRCA2.
Reason: Nucleoplasm localization during checkpoint signaling.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5685341 |
ACCEPT |
Summary: Reactome - BCDX2 complex stabilizes RAD51 filament.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5685838 |
ACCEPT |
Summary: Reactome - CX3 complex binds D-loop.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5686410 |
ACCEPT |
Summary: Reactome - BLM mediates dissolution of double Holliday junction.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5686440 |
ACCEPT |
Summary: Reactome - MUS81:EME1,EME2 cleaves D-loop.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5686469 |
ACCEPT |
Summary: Reactome - Resolution of D-loops.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5686483 |
ACCEPT |
Summary: Reactome - Resolution of Holliday junctions.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5693539 |
ACCEPT |
Summary: Reactome - Ligation of DNA and Holliday structure formation.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5693561 |
ACCEPT |
Summary: Reactome - RAD51 binds BRCA2 at resected DSBs.
Reason: Core nucleoplasm localization for HR.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5693584 |
ACCEPT |
Summary: Reactome - Cleavage of Holliday junctions.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5693589 |
ACCEPT |
Summary: Reactome - D-loop dissociation and strand annealing.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5693593 |
ACCEPT |
Summary: Reactome - D-loop extension by DNA polymerases.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5693620 |
ACCEPT |
Summary: Reactome - D-loop formation mediated by PALB2, BRCA2 and RAD51.
Reason: Core nucleoplasm localization for HR function.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9701199 |
ACCEPT |
Summary: Reactome - Defective D-loop formation due to BRCA1 loss.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9704330 |
ACCEPT |
Summary: Reactome - Defective D-loop formation due to PALB2 loss.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9704408 |
ACCEPT |
Summary: Reactome - Defective D-loop formation.
Reason: Nucleoplasm localization.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9853389 |
ACCEPT |
Summary: Reactome - FIGNL1 binds RAD51.
Reason: Nucleoplasm localization.
|
|
GO:0005813
centrosome
|
IDA
PMID:21276791 Homologous recombination proteins are associated with centro... |
KEEP AS NON CORE |
Summary: HR proteins including BRCA2 associate with centrosomes.
Reason: Centrosome localization is secondary to nuclear DNA repair function.
Supporting Evidence:
PMID:21276791
Epub 2011 Jan 27. Homologous recombination proteins are associated with centrosomes and are required for mitotic stability.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-9709273 |
ACCEPT |
Summary: Reactome - BRCA2 translocates to nucleus.
Reason: Nucleoplasm localization.
|
|
GO:0051298
centrosome duplication
|
IMP
PMID:17286961 Interference with BRCA2, which localizes to the centrosome d... |
KEEP AS NON CORE |
Summary: BRCA2 interference leads to abnormal centrosome duplication.
Reason: BRCA2 affects centrosome function but this is secondary to HR.
Supporting Evidence:
PMID:17286961
Interference with BRCA2, which localizes to the centrosome during S and early M phase, leads to abnormal nuclear division.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IDA
PMID:9126734 Transcriptional activation functions in BRCA2. |
KEEP AS NON CORE |
Summary: BRCA2 contains transcriptional activation functions in its N-terminus.
Reason: BRCA2 has transcriptional activation activity but this is not its primary function.
Supporting Evidence:
PMID:9126734
Transcriptional activation functions in BRCA2.
|
|
GO:0033593
BRCA2-MAGE-D1 complex
|
IDA
PMID:15930293 BRCA2 suppresses cell proliferation via stabilizing MAGE-D1. |
KEEP AS NON CORE |
Summary: BRCA2 forms complex with MAGE-D1 to suppress cell proliferation.
Reason: This complex has anti-proliferative function but is not central to BRCA2's HR role.
Supporting Evidence:
PMID:15930293
BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
|
|
GO:0033600
negative regulation of mammary gland epithelial cell proliferation
|
IDA
PMID:15930293 BRCA2 suppresses cell proliferation via stabilizing MAGE-D1. |
KEEP AS NON CORE |
Summary: BRCA2-MAGE-D1 complex suppresses mammary epithelial proliferation.
Reason: Anti-proliferative function is tissue-specific and secondary.
Supporting Evidence:
PMID:15930293
BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
|
|
GO:0005634
nucleus
|
IDA
PMID:17286961 Interference with BRCA2, which localizes to the centrosome d... |
ACCEPT |
Summary: Nuclear localization during S and early M phase.
Reason: Core nuclear localization.
Supporting Evidence:
PMID:17286961
Interference with BRCA2, which localizes to the centrosome during S and early M phase, leads to abnormal nuclear division.
|
|
GO:0005634
nucleus
|
IDA
PMID:9560268 The BRC repeats in BRCA2 are critical for RAD51 binding and ... |
ACCEPT |
Summary: Nuclear localization for RAD51 binding.
Reason: Core nuclear localization.
Supporting Evidence:
PMID:9560268
The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment.
|
|
GO:0005634
nucleus
|
IDA
PMID:9774970 Stable interaction between the products of the BRCA1 and BRC... |
ACCEPT |
Summary: Nuclear localization in mitotic and meiotic cells.
Reason: Core nuclear localization.
Supporting Evidence:
PMID:9774970
Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.
|
|
GO:0005813
centrosome
|
IDA
PMID:17286961 Interference with BRCA2, which localizes to the centrosome d... |
KEEP AS NON CORE |
Summary: Centrosome localization during S and early M phase.
Reason: Secondary localization.
Supporting Evidence:
PMID:17286961
Interference with BRCA2, which localizes to the centrosome during S and early M phase, leads to abnormal nuclear division.
|
|
GO:0006289
nucleotide-excision repair
|
IMP
PMID:16845393 The role of BRCA2 in replication-coupled DNA interstrand cro... |
KEEP AS NON CORE |
Summary: BRCA2 role in replication-coupled DNA interstrand cross-link repair.
Reason: BRCA2's primary role is HR, but it participates in ICL repair which involves NER components.
Supporting Evidence:
PMID:16845393
Jul 16. The role of BRCA2 in replication-coupled DNA interstrand cross-link repair in vitro.
|
|
GO:0006302
double-strand break repair
|
IMP
PMID:16845393 The role of BRCA2 in replication-coupled DNA interstrand cro... |
ACCEPT |
Summary: BRCA2 required for DSB repair in ICL repair context.
Reason: DSB repair is a core BRCA2 function.
Supporting Evidence:
PMID:16845393
Jul 16. The role of BRCA2 in replication-coupled DNA interstrand cross-link repair in vitro.
|
|
GO:0030141
secretory granule
|
IDA
PMID:8589722 BRCA1 is secreted and exhibits properties of a granin. |
UNDECIDED |
Summary: Old study claiming BRCA1 secretion and granin properties. Reference seems to be about BRCA1 not BRCA2.
Reason: This reference (PMID:8589722) appears to be about BRCA1, not BRCA2. Possible annotation error. Needs verification.
Supporting Evidence:
PMID:8589722
BRCA1 is secreted and exhibits properties of a granin.
|
|
GO:0000730
DNA recombinase assembly
|
IEA | NEW |
Summary: BRCA2 facilitates RAD51 recombinase assembly on single-stranded DNA by targeting RAD51 to ssDNA over dsDNA, enabling RAD51 to displace RPA and stabilizing RAD51-ssDNA nucleoprotein filaments.
Reason: BRCA2 promotes assembly of RAD51 onto single-stranded DNA. This is a core function essential for homologous recombination repair. Well-supported by biochemical studies.
Supporting Evidence:
file:human/BRCA2/BRCA2-deep-research-falcon.md
BRCA2 mediates homologous recombination (HR) by loading and stabilizing the recombinase RAD51 on resected single-stranded DNA (ssDNA) to form the presynaptic filament required for homology search and strand exchange
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GO:0042148
DNA strand invasion
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IEA | NEW |
Summary: BRCA2 facilitates strand invasion during homologous recombination by promoting RAD51 nucleoprotein filament formation. BRCA2 may also play a role in the extension step after strand invasion at replication-dependent DSBs.
Reason: BRCA2 promotes RAD51 filament formation which is essential for strand invasion during HR. Working with PALB2, BRCA2 is involved in POLH localization at collapsed forks and DNA polymerization.
Supporting Evidence:
file:human/BRCA2/BRCA2-deep-research-falcon.md
D-loop formation mediated by PALB2, BRCA2 and RAD51
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The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Comprehensive Research Report on Human BRCA2 (UniProt P51587)
Plan and identity verification
- We verified the target identity: BRCA2, UniProt P51587, Homo sapiens, with aliases FANCD1/FACD, is the human breast cancer type 2 susceptibility protein. Core domains (BRC repeats; DNA-binding domain with OB folds and tower; C-terminal recombinase-binding region) and DSS1 binding described below match contemporary literature (including 2023 primary work) and reviews focused on BRCA2 structure–function, HR repair, and fork protection (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 2-4, chanteau2025thefunctionalanalysis pages 55-60, chanteau2025thefunctionalanalysis pages 60-64).
1) Key concepts and definitions
- Primary function. BRCA2 is a genome maintenance factor that mediates homologous recombination (HR) by loading and stabilizing the recombinase RAD51 on resected single-stranded DNA (ssDNA) to form the presynaptic filament required for homology search and strand exchange (kumpula2024theroleof pages 35-38, shah2025homologousrecombinationdeficiency pages 1-3).
- Fork protection. Beyond DSB repair, BRCA2 stabilizes RAD51 on stalled/reversed replication forks to prevent nucleolytic degradation (e.g., by MRE11) and to promote restart, a function genetically and biochemically separable but coordinated with HR (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 2-4).
- HRD and synthetic lethality. BRCA2 loss-of-function underlies the homologous recombination deficiency (HRD) state, which confers sensitivity to platinum agents and PARP inhibitors via synthetic lethality, an established precision-oncology paradigm (shah2025homologousrecombinationdeficiency pages 1-3, shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 28-29).
2) Molecular architecture, partners, and mechanisms
- Domain architecture.
• Central DNA-binding domain (DBD). The canonical DBD comprises a helical domain (HD), three OB folds (OB1–OB3), and a tower domain appendage. It binds DNA with high affinity and preferentially engages ssDNA in concert with DSS1; most pathogenic missense variants cluster in exons encoding this DBD (exons 15–26), aligning with functional hotspots resolved by saturation genome editing (SGE) (chanteau2025thefunctionalanalysis pages 60-64, chanteau2025thefunctionalanalysis pages 55-60, couch2023saturationgenomeeditingbased pages 1-4).
• C-terminal recombinase-binding region (CTRB; exon 27). The CTRB (residues ~3260–3337) is intrinsically disordered but contains conserved FxxP motifs and a basic cluster. It binds both ssDNA and dsDNA and directly engages oligomeric RAD51. CTRB alone stimulates RAD51-mediated DNA strand exchange and enables RAD51 to utilize RPA-coated ssDNA; CTRB cooperates with the BRC repeats and DBD to promote RPA-to-RAD51 exchange and is critical for HR and fork protection from MRE11 (mirin-sensitive) degradation (Nature Communications, Jan 2023; https://doi.org/10.1038/s41467-023-36211-x) (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, kwon2023dnabindingand pages 2-4).
• BRC repeats. Eight internal BRC motifs bind RAD51 with varying affinities; they modulate RAD51 oligomerization, promote ATP-bound RAD51, and seed presynaptic filament assembly together with DBD/CTRB (chanteau2025thefunctionalanalysis pages 55-60, chanteau2025thefunctionalanalysis pages 60-64).
• DSS1-binding. A positively charged surface across HD/OB1 binds DSS1, which regulates DBD DNA interactions—enhancing ssDNA preference and constraining dsDNA binding, thereby promoting RPA→RAD51 exchange on ssDNA; DSS1 loss phenocopies BRCA2 deficiency in HR (chanteau2025thefunctionalanalysis pages 168-172, chanteau2025thefunctionalanalysis pages 60-64).
- Principal partners and pathway context.
• RAD51 is the direct recombinase client; BRCA2’s BRC repeats and CTRB cooperate to load/stabilize RAD51 on ssDNA and at reversed forks (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, kwon2023dnabindingand pages 2-4).
• PALB2 and BRCA1–BARD1 coordinate resection and BRCA2 delivery to damage sites; BRCA1–BARD1 also toggles between resection and fork protection contexts, with RAD51 levels contributing to functional balance (review context) (shah2025homologousrecombinationdeficiency pages 1-3, chanteau2025thefunctionalanalysis pages 55-60).
• DSS1 stabilizes BRCA2 and facilitates DBD functions (chanteau2025thefunctionalanalysis pages 168-172, chanteau2025thefunctionalanalysis pages 60-64).
• Meiosis: BRCA2 collaborates with meiotic factors (e.g., MEILB2–BRME1) to load recombinases (contextual review evidence) (shah2025homologousrecombinationdeficiency pages 1-3).
- Mechanistic synthesis. BRCA2 promotes RAD51 nucleation and growth on RPA-coated ssDNA using multivalent contacts (BRCs, DBD/OB folds, CTRB), then preserves replication forks by stabilizing RAD51 on reversed forks, preventing pathological resection and enabling restart (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, chanteau2025thefunctionalanalysis pages 55-60, chanteau2025thefunctionalanalysis pages 60-64).
3) Subcellular localization and regulation
- BRCA2 is predominantly nuclear and accumulates at DNA double-strand breaks, ssDNA gaps, and stressed/reversed replication forks. Its engagement is coordinated with cell-cycle DNA repair programs and with BRCA1–BARD1/CtIP-mediated resection to create the RAD51 substrate (shah2025homologousrecombinationdeficiency pages 1-3, chanteau2025thefunctionalanalysis pages 55-60).
4) Disease relevance and penetrance; second primary risks
- Cancer predisposition. Pathogenic BRCA2 variants confer high lifetime breast cancer risk and elevated risks for ovarian, prostate, and pancreatic cancers. Contemporary summaries report cumulative breast cancer risk on the order of ~69% and ovarian cancer ~17% by age 80 for protein-truncating variants, and that biallelic BRCA2 mutations cause Fanconi anemia (FANCD1), consistent with essential HR functions (kumpula2024theroleof pages 35-38).
- Variant–disease mapping (2023–2024). SGE across exons 15–26 (DBD hotspot) functionally classified 7013 single nucleotide variants (SNVs), with 955 functionally abnormal. Functionally abnormal missense variants were associated with increased breast/ovarian cancer risk (OR ~3.9) and tumors showed higher LOH (86% vs 26% for functionally normal), providing powerful evidence to reclassify many VUS and to refine risk management (Dec 2023 preprint; https://doi.org/10.21203/rs.3.rs-3736200/v1) (couch2023saturationgenomeeditingbased pages 1-4).
- Second primary risks. Contemporary large-scale HRD/BRCA-focused reviews and risk syntheses support elevated second primary risks in BRCA1/2 carriers, notably contralateral breast cancer and ovarian cancer after a first breast cancer; risk magnitudes vary by gene and sex (contextual review) (shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 28-29).
5) Recent developments and latest research (emphasis 2023–2024)
- Structural–mechanistic advance: BRCA2 CTRB (exon 27) mechanistic dissection. High-quality 2023 work demonstrated direct DNA binding and RAD51 engagement by CTRB, and its cooperation with BRC/DBD in presynaptic filament formation and fork protection; separation-of-function mutants showed DNA-binding and RAD51-binding motifs are both required (Nature Communications, Jan 2023; https://doi.org/10.1038/s41467-023-36211-x) (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, kwon2023dnabindingand pages 2-4).
- High-throughput variant interpretation: SGE of BRCA2 DBD. A Dec 2023 SGE study functionally assayed 97% of possible SNVs across exons 15–26, enabling classification of 700 SNVs as pathogenic/likely pathogenic and 4862 as benign/likely benign when integrated with ClinGen/ACMG frameworks—substantially reducing VUS burden (https://doi.org/10.21203/rs.3.rs-3736200/v1) (couch2023saturationgenomeeditingbased pages 1-4).
- HRD testing landscape and variability. Reviews from 2024–2025 synthesize inter-assay discordances across genomic HRD tests (e.g., gLOH thresholds, scar scores, HRDetect) and argue for complementary functional assays such as RAD51 foci to improve predictive value for PARP inhibitor benefit (shah2025homologousrecombinationdeficiency pages 28-29, shah2025homologousrecombinationdeficiency pages 8-9, shah2025homologousrecombinationdeficiency pages 25-26).
6) Current applications and real-world implementation
- Germline/somatic testing. BRCA2 testing guides prevention (enhanced surveillance, risk-reducing surgery) and treatment selection (PARP inhibitors, platinum) in breast, ovarian, prostate, and pancreatic cancers; non-BRCA HRD markers can extend PARP benefit but require robust validation (kumpula2024theroleof pages 35-38, shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 28-29).
- PARP inhibitor indications. HRD-positive and particularly BRCA1/2-mutated high-grade serous ovarian carcinoma (HGSOC) show high response rates (e.g., 60–80% ORR reported) and progression-free survival benefits on PARPi; similar benefits are seen in subsets of breast, prostate, and pancreatic cancers (review synthesis) (shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 28-29).
- HRD assays in practice. Commercial genomic-scarring assays (e.g., myChoice CDx, FoundationOne CDx) and research algorithms (e.g., HRDetect) are used to infer HRD, but exhibit notable variability, emphasizing the value of integrating genomic scars with functional RAD51 assays and careful thresholding for clinical decision-making (shah2025homologousrecombinationdeficiency pages 28-29, shah2025homologousrecombinationdeficiency pages 25-26).
7) Expert opinions and analysis from authoritative sources
- Mechanistic expert synthesis. The 2023 Nature Communications study provides direct molecular evidence for CTRB’s dual DNA/RAD51 engagement as integral to HR and fork protection, refining the canonical model of BRCA2-mediated RAD51 loading and fork stabilization (https://doi.org/10.1038/s41467-023-36211-x) (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, kwon2023dnabindingand pages 2-4).
- Variant-interpretation ecosystem. The 2023 SGE preprint outlines a comprehensive framework aligning functional scores with ClinGen/ACMG classification, supporting widespread clinical adoption to resolve BRCA2 DBD missense VUS (https://doi.org/10.21203/rs.3.rs-3736200/v1) (couch2023saturationgenomeeditingbased pages 1-4). Parallel SGE/DMS efforts on RAD51C and guidance for functional evidence (PS3/BS3) underscore a rapidly maturing field (olveraleon2024comprehensivesaturationgenome pages 26-27).
- HRD testing consensus gaps. Contemporary HRD reviews highlight the need for assay harmonization, improved detection of non-BRCA HRD, and integration of functional biomarkers to optimize patient selection for PARPi and combinations (shah2025homologousrecombinationdeficiency pages 28-29, shah2025homologousrecombinationdeficiency pages 8-9, shah2025homologousrecombinationdeficiency pages 25-26).
8) Relevant statistics and data from recent studies
- BRCA2 penetrance and spectrum. Summaries from recent hereditary-breast cancer research report cumulative breast cancer risk ~69% and ovarian cancer ~17% to age 80 for protein-truncating BRCA2 variants; BRCA1/2 account for ~15–20% of hereditary breast cancer; biallelic BRCA2 causes FANCD1 (kumpula2024theroleof pages 35-38).
- Functional classification yield from SGE. 7013 BRCA2 DBD SNVs functionally scored; 955 abnormal; abnormal missense pool associated with increased breast/ovarian cancer risk (OR 3.89, 95% CI 2.77–5.51); LOH in 86% of tumors for abnormal variants vs 26% for normal—substantially enabling clinical reclassification (Dec 2023; https://doi.org/10.21203/rs.3.rs-3736200/v1) (couch2023saturationgenomeeditingbased pages 1-4).
- HRD/PARPi outcomes. Reviews collating trial and practice data report high PARPi response rates in BRCA1/2-mutated HGSOC (e.g., 60–80% ORR) and PFS improvements; HRD-positive (non-BRCA) cohorts derive benefit but with variable effect sizes; resistance mechanisms include BRCA reversion and replication fork stabilization (shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 28-29).
9) Where BRCA2 works in the cell and pathway placement
- Site of action. BRCA2 functions in the nucleus at resected DSBs, ssDNA gaps, and reversed forks—physically loading and stabilizing RAD51 onto ssDNA and protecting regressed forks from MRE11-mediated degradation (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, chanteau2025thefunctionalanalysis pages 55-60).
- Pathways. It operates in the RAD51-dependent HR pathway downstream of MRN/CtIP/EXO1 resection and within replication-stress responses that promote fork reversal and protection—interfacing with BRCA1–BARD1, PALB2, RAD51 paralogs, and DSS1 (shah2025homologousrecombinationdeficiency pages 1-3, chanteau2025thefunctionalanalysis pages 55-60, chanteau2025thefunctionalanalysis pages 168-172).
Key artifact (summary table)
| Category | Specifics | Key Evidence / Notes | Year | Source (journal/name) with URL |
|---|---|---|---:|---|
| Domains | BRC repeats (multiple BRC motifs), DNA-binding domain (DBD) with OB folds + tower domain, DSS1-binding site, C-terminal Recombinase-Binding region (CTRB / exon 27) | Functional mapping of the DBD hotspot (exons 15–26) by saturation genome editing; domain roles inferred from functional assays linking DBD/CTRB to RAD51 engagement and fork protection (SGE shows DBD missense LOF associates with cancer risk) (couch2023saturationgenomeeditingbased pages 1-4, kumpula2024theroleof pages 35-38, shah2025homologousrecombinationdeficiency pages 1-3) | 2023–2024 | Couch et al. (2023) SGE preprint — https://doi.org/10.21203/rs.3.rs-3736200/v1; Kumpula 2024 (role summary) (couch2023saturationgenomeeditingbased pages 1-4, kumpula2024theroleof pages 35-38) |
| Principal partners | RAD51 (direct binding/filament stabilization), PALB2 (bridging to BRCA1), BRCA1–BARD1 (resection/protection axis), DSS1 (stabilizes BRCA2), meiosis-specific MEILB2–BRME1 interaction | BRCA2 mediates RAD51 loading; reviews and functional studies list PALB2/BRCA1–BARD1/DSS1 as core interactors; RAD51-paralog and RAD51C functional mapping work supports collaboration in filament dynamics (shah2025homologousrecombinationdeficiency pages 1-3, olveraleon2024comprehensivesaturationgenome pages 26-27) | 2024–2025 | Shah et al. (2025) HRD review preprint — https://doi.org/10.20944/preprints202504.0229.v1; Olvera-León et al. (RAD51C SGE) 2024 (shah2025homologousrecombinationdeficiency pages 1-3, olveraleon2024comprehensivesaturationgenome pages 26-27) |
| Core functions | Loads/stabilizes RAD51 on RPA-coated ssDNA for homologous recombination (HDR); protects stalled/reversed replication forks from nucleolytic degradation (fork protection) | Mechanistic role in RAD51 loading and fork protection is central to BRCA2 tumor-suppressor activity; DBD/CTRB perturbation → defective HDR and increased cancer association in SGE data (couch2023saturationgenomeeditingbased pages 1-4, kumpula2024theroleof pages 35-38, shah2025homologousrecombinationdeficiency pages 1-3) | 2023–2025 | Kumpula 2024 (functional summary) & Couch et al. (2023) SGE (kumpula2024theroleof pages 35-38, couch2023saturationgenomeeditingbased pages 1-4) |
| Cellular localization & regulation | Predominantly nuclear; recruited to DNA damage sites and stalled forks; activity coordinated with cell-cycle DNA repair programs and with PALB2/BRCA1-mediated resection machinery | Reviews and mechanistic summaries describe BRCA2 acting at DSBs and replication forks with cell-cycle-dependent repair engagement; implications for HRD phenotype and therapy response (shah2025homologousrecombinationdeficiency pages 1-3, kumpula2024theroleof pages 35-38) | 2024–2025 | Shah et al. (2025) review — https://doi.org/10.20944/preprints202504.0229.v1 (shah2025homologousrecombinationdeficiency pages 1-3) |
| Key 2023–2024 developments | 1) Saturation genome editing (SGE) of BRCA2 DBD enabling large-scale functional classification of SNVs; 2) Growing recognition of HRD assay variability and need for harmonization; 3) Functional RAD51 assays (RAD51 foci) as complements to genomic HRD tests | SGE provided high-resolution functional scores linking DBD variants to pathogenicity and LOH in tumors; HRD-testing reviews highlight assay discordance and the value of combining genomic scars with functional readouts to predict PARPi response (couch2023saturationgenomeeditingbased pages 1-4, shah2025homologousrecombinationdeficiency pages 28-29, shah2025homologousrecombinationdeficiency pages 8-9, shah2025homologousrecombinationdeficiency pages 25-26) | 2023–2024 (SGE 2023; HRD assay discussions 2024–2025) | Couch et al. (2023) SGE preprint https://doi.org/10.21203/rs.3.rs-3736200/v1; Shah et al. (2025) HRD review https://doi.org/10.20944/preprints202504.0229.v1 (couch2023saturationgenomeeditingbased pages 1-4, shah2025homologousrecombinationdeficiency pages 28-29) |
| Clinical applications | Germline/somatic BRCA2 testing guides risk management (surveillance, risk-reducing surgery) and therapy (PARP inhibitors in breast/ovarian/prostate/pancreatic cancer); HRD assays (genomic scars, gLOH, HRDetect) used to expand PARPi indications but show inter-assay variability | Penetrance & risk estimates summarized in recent reviews; real-world studies show variable testing and PARPi uptake; HRD assays predict PARPi benefit but discordance across platforms necessitates integrated approaches (kumpula2024theroleof pages 35-38, shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 28-29) | 2023–2024 (clinical guideline activity) | Kumpula 2024 (penetrance/clinical impact) and Shah et al. (2025) HRD/clinical assay discussion (kumpula2024theroleof pages 35-38, shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 28-29) |
Table: Compact table summarizing BRCA2 domains, partners, core functions, localization, recent 2023–2024 developments, and clinical applications with key supporting evidence (context IDs).
URLs and publication dates (selection)
- Kwon et al., Nature Communications, Jan 2023. URL: https://doi.org/10.1038/s41467-023-36211-x (CTRB/RAD51–DNA engagement; HR/fork protection) (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, kwon2023dnabindingand pages 2-4).
- Couch et al., Research Square preprint, Dec 2023. URL: https://doi.org/10.21203/rs.3.rs-3736200/v1 (BRCA2 DBD SGE; variant classification and clinical integration) (couch2023saturationgenomeeditingbased pages 1-4).
- Shah et al., Preprints (MDPI), Apr 2025. URL: https://doi.org/10.20944/preprints202504.0229.v1 (HRD biomarker landscape, assay variability, PARPi implications; bridges 2023–2024 literature) (shah2025homologousrecombinationdeficiency pages 28-29, shah2025homologousrecombinationdeficiency pages 8-9, shah2025homologousrecombinationdeficiency pages 25-26, shah2025homologousrecombinationdeficiency pages 26-28, shah2025homologousrecombinationdeficiency pages 1-3).
Conclusion
Human BRCA2 (P51587) is a nuclear HR mediator and fork-protection factor whose multivalent architecture—BRC repeats, OB folds/tower DBD, and CTRB—coordinates RAD51 loading on ssDNA and stabilization at stalled forks. Recent (2023–2024) advances provide high-resolution functional maps (SGE) of DBD variants for clinical interpretation and mechanistic dissection of the CTRB’s dual DNA/RAD51-binding roles in HR and fork preservation. Clinically, BRCA2 underpins HRD-directed therapy: germline/somatic testing informs prevention and selection of PARP inhibitors and platinum, though HRD test heterogeneity argues for integrated genomic and functional biomarkers. These contemporary data refine mechanistic understanding and improve clinical decision-making for individuals with BRCA2 variants and for tumors exhibiting BRCA2-associated HRD (kwon2023dnabindingand pages 1-2, kwon2023dnabindingand pages 8-10, couch2023saturationgenomeeditingbased pages 1-4, shah2025homologousrecombinationdeficiency pages 28-29).
References
(kwon2023dnabindingand pages 1-2): Youngho Kwon, Heike Rösner, Weixing Zhao, Platon Selemenakis, Zhuoling He, Ajinkya S. Kawale, Jeffrey N. Katz, Cody M. Rogers, Francisco E. Neal, Aida Badamchi Shabestari, Valdemaras Petrosius, Akhilesh K. Singh, Marina Z. Joel, Lucy Lu, Stephen P. Holloway, Sandeep Burma, Bipasha Mukherjee, Robert Hromas, Alexander Mazin, Claudia Wiese, Claus S. Sørensen, and Patrick Sung. Dna binding and rad51 engagement by the brca2 c-terminus orchestrate dna repair and replication fork preservation. Nature Communications, Jan 2023. URL: https://doi.org/10.1038/s41467-023-36211-x, doi:10.1038/s41467-023-36211-x. This article has 49 citations and is from a highest quality peer-reviewed journal.
(kwon2023dnabindingand pages 2-4): Youngho Kwon, Heike Rösner, Weixing Zhao, Platon Selemenakis, Zhuoling He, Ajinkya S. Kawale, Jeffrey N. Katz, Cody M. Rogers, Francisco E. Neal, Aida Badamchi Shabestari, Valdemaras Petrosius, Akhilesh K. Singh, Marina Z. Joel, Lucy Lu, Stephen P. Holloway, Sandeep Burma, Bipasha Mukherjee, Robert Hromas, Alexander Mazin, Claudia Wiese, Claus S. Sørensen, and Patrick Sung. Dna binding and rad51 engagement by the brca2 c-terminus orchestrate dna repair and replication fork preservation. Nature Communications, Jan 2023. URL: https://doi.org/10.1038/s41467-023-36211-x, doi:10.1038/s41467-023-36211-x. This article has 49 citations and is from a highest quality peer-reviewed journal.
(chanteau2025thefunctionalanalysis pages 55-60): A Chanteau. The functional analysis of canonical and non-canonical brca2 in homologous recombination repair. Unknown journal, 2025.
(chanteau2025thefunctionalanalysis pages 60-64): A Chanteau. The functional analysis of canonical and non-canonical brca2 in homologous recombination repair. Unknown journal, 2025.
(kumpula2024theroleof pages 35-38): T Kumpula. The role of rare copy number variants and other candidate alleles in hereditary breast cancer susceptibility. Unknown journal, 2024.
(shah2025homologousrecombinationdeficiency pages 1-3): Bhaumik Shah, Muhammad Hussain, and Anjali Seth. Homologous recombination deficiency in ovarian and breast cancers: biomarkers, diagnosis and treatment. Apr 2025. URL: https://doi.org/10.20944/preprints202504.0229.v1, doi:10.20944/preprints202504.0229.v1.
(shah2025homologousrecombinationdeficiency pages 26-28): Bhaumik Shah, Muhammad Hussain, and Anjali Seth. Homologous recombination deficiency in ovarian and breast cancers: biomarkers, diagnosis and treatment. Apr 2025. URL: https://doi.org/10.20944/preprints202504.0229.v1, doi:10.20944/preprints202504.0229.v1.
(shah2025homologousrecombinationdeficiency pages 28-29): Bhaumik Shah, Muhammad Hussain, and Anjali Seth. Homologous recombination deficiency in ovarian and breast cancers: biomarkers, diagnosis and treatment. Apr 2025. URL: https://doi.org/10.20944/preprints202504.0229.v1, doi:10.20944/preprints202504.0229.v1.
(couch2023saturationgenomeeditingbased pages 1-4): Fergus Couch, Huaizhi Huang, Chunling Hu, Jie Na, Steven Hart, Rohan Gnanaolivu, Mohamed Abozaid, Tara Rao, Yohannes Tecleab, Tina Pesaran, Paulo Lyra, Rachid Karam, Siddhartha Yadav, Susan Domchek, Miguel de la Hoya, Mark Robson, Miika Mehine, Chaitanya Bandlamudi, Diana Mandelker, Alvaro Monteiro, Nicholas Boddicker, Wenan Chen, and Marcy Richardson. Saturation genome editing-based functional evaluation and clinical classification of brca2 single nucleotide variants. Dec 2023. URL: https://doi.org/10.21203/rs.3.rs-3736200/v1, doi:10.21203/rs.3.rs-3736200/v1.
(kwon2023dnabindingand pages 8-10): Youngho Kwon, Heike Rösner, Weixing Zhao, Platon Selemenakis, Zhuoling He, Ajinkya S. Kawale, Jeffrey N. Katz, Cody M. Rogers, Francisco E. Neal, Aida Badamchi Shabestari, Valdemaras Petrosius, Akhilesh K. Singh, Marina Z. Joel, Lucy Lu, Stephen P. Holloway, Sandeep Burma, Bipasha Mukherjee, Robert Hromas, Alexander Mazin, Claudia Wiese, Claus S. Sørensen, and Patrick Sung. Dna binding and rad51 engagement by the brca2 c-terminus orchestrate dna repair and replication fork preservation. Nature Communications, Jan 2023. URL: https://doi.org/10.1038/s41467-023-36211-x, doi:10.1038/s41467-023-36211-x. This article has 49 citations and is from a highest quality peer-reviewed journal.
(chanteau2025thefunctionalanalysis pages 168-172): A Chanteau. The functional analysis of canonical and non-canonical brca2 in homologous recombination repair. Unknown journal, 2025.
(shah2025homologousrecombinationdeficiency pages 8-9): Bhaumik Shah, Muhammad Hussain, and Anjali Seth. Homologous recombination deficiency in ovarian and breast cancers: biomarkers, diagnosis and treatment. Apr 2025. URL: https://doi.org/10.20944/preprints202504.0229.v1, doi:10.20944/preprints202504.0229.v1.
(shah2025homologousrecombinationdeficiency pages 25-26): Bhaumik Shah, Muhammad Hussain, and Anjali Seth. Homologous recombination deficiency in ovarian and breast cancers: biomarkers, diagnosis and treatment. Apr 2025. URL: https://doi.org/10.20944/preprints202504.0229.v1, doi:10.20944/preprints202504.0229.v1.
(olveraleon2024comprehensivesaturationgenome pages 26-27): R Olvera-León, F Zhang, V Offord, Y Zhao, and HK Tan. Comprehensive saturation genome editing of rad51c provides precise functional classification within a spectrum of variant effects. Unknown journal, 2024.
BRCA2 (breast cancer type 2 susceptibility protein, also known as Fanconi anemia group D1 protein) is a large, multifunctional tumor suppressor protein encoded on human chromosome 13 that serves as a critical mediator in homologous recombination-based DNA repair, replication fork protection, and genome stability maintenance. The BRCA2 protein (3,418 amino acids, approximately 384 kDa) functions primarily through a sophisticated molecular mechanism in which it acts as a recombination mediator by facilitating the recruitment and assembly of the RAD51 recombinase onto single-stranded DNA generated during DNA damage or replication stress, thereby enabling high-fidelity double-strand break repair through homologous recombination and interstrand crosslink repair. Beyond its canonical roles in recombination-mediated repair, BRCA2 participates in cell cycle checkpoint control, protects stalled replication forks from nucleolytic degradation through distinct mechanisms, and undergoes dynamic cell cycle-regulated modulation of its activity to coordinate DNA repair processes with cellular proliferation. The protein localizes exclusively to the cell nucleus through three conserved nuclear localization signals in its C-terminus, interacts with multiple partner proteins including PALB2, RAD51, DMC1, and DSS1 through distinct protein domains, and when functionally compromised through germline mutations, confers substantially elevated lifetime risks of breast cancer (>60%), ovarian cancer (13-29%), and pancreatic cancer (5-10%), establishing BRCA2 as a classical tumor suppressor gene whose loss of function drives genomic instability and malignant transformation.
The BRCA2 protein is an exceptionally large molecule composed of 3,418 amino acids that exhibits a highly modular architecture with distinct functional domains arranged in a linear sequence along the protein backbone[1][2]. Structurally, the protein functions as a dimer, a configuration that has been revealed through three-dimensional electron microscopy reconstructions and biochemical analysis[2]. The dimeric assembly of BRCA2 is not merely a passive oligomerization but rather a functionally significant state that enables the simultaneous recruitment of multiple copies of the RAD51 recombinase, with two oppositely-oriented sets of RAD51 molecules binding to each BRCA2 dimer[2]. This architectural arrangement appears to be critical for the protein's ability to nucleate RAD51 filament formation efficiently at multiple sites along single-stranded DNA, establishing a molecular mechanism by which BRCA2 can coordinate the assembly of the recombination machinery. The existence of these different oligomeric states—monomeric and dimeric forms—is not static but rather dynamically regulated by binding partners such as DSS1 (a small acidic protein that stabilizes the monomeric form) and single-stranded DNA, suggesting a model in which the oligomerization state of BRCA2 itself may be a regulated aspect of its cellular function[51].
The most extensively studied functional domain of BRCA2 is the central region containing eight tandem BRC (BRCA2 repeat containing) repeats, which spans approximately 1,127 amino acids within exon 11 and constitutes the primary interaction interface with the RAD51 recombinase[1][13][43]. These eight BRC repeats are arranged in a highly ordered manner and are highly conserved among mammalian species, suggesting ancient evolutionary importance for their functions[16][43]. The BRC repeats display a hierarchical organization with distinct functional specialization, as the upstream repeats BRC1-4 bind to free RAD51 monomers with high affinity and serve to stimulate RAD51-ssDNA complex formation while simultaneously inhibiting RAD51 binding to double-stranded DNA, thereby creating selectivity for the repair substrate[16][43]. In contrast, the downstream repeats BRC5-8 exhibit lower affinity for free RAD51 but preferentially bind to and stabilize RAD51 nucleoprotein filaments that have already assembled on ssDNA, supporting filament elongation and preventing disassembly[16][43]. This functional dichotomy suggests an evolutionary optimization in which BRC1-4 serve primarily to nucleate RAD51 filament assembly at the initiating stage, while BRC5-8 function to maintain and extend the growing filament during the critical early stages of strand invasion and homologous pairing.
The specificity of BRC repeat-RAD51 interaction has been illuminated by structural studies demonstrating that each BRC motif directly mimics the structure of a RAD51 monomer at its polymerization interface, allowing RAD51 molecules to bind to BRC repeats in a manner that facilitates subsequent protein-protein interactions and cooperative assembly[1][13]. The binding occurs through a series of hydrophobic and hydrophilic interactions that stabilize a β-hairpin structure of the BRC sequence against the oligomerization surface of RAD51[8]. Importantly, not all eight BRC repeats function identically; the first four BRC repeats are substantially more conserved across mammalian species and bind RAD51 with markedly higher affinity than the latter four repeats, consistent with biochemical evidence that demonstrates progressive decreases in RAD51 binding affinity from BRC1 through BRC8[16]. Some evidence suggests that the variable affinity among BRC repeats may reflect their specialized roles in sequestering or releasing RAD51 under different cellular conditions, representing an elegant molecular mechanism for fine-tuning the activity of this essential recombination protein.
The C-terminal region of BRCA2 (CTD), spanning approximately 710 amino acids from residues 2,481 to 3,190, comprises the second major structural and functional element of the protein and contains the primary DNA-binding capacity[2][14]. This domain exhibits a complex hierarchical organization consisting of an α-helical domain located in the N-terminal portion followed by three oligonucleotide/oligosaccharide-binding (OB) folds designated OB1, OB2, and OB3[2][14]. The three OB folds within the BRCA2 C-terminal domain function cooperatively to achieve high-affinity single-stranded DNA binding, with OB2 and OB3 contributing more substantially to ssDNA binding affinity than OB1, consistent with structural and sequence conservation patterns[2][14]. The DNA-binding domain is capable of binding both single-stranded and double-stranded DNA, though it exhibits a clear preference for single-stranded DNA substrates[2]. Importantly, the BRCA2 C-terminal domain requires approximately 40 nucleotides of single-stranded DNA for weak binding and more than 70 nucleotides for maximal binding affinity, indicating that the domain functions optimally with relatively extended DNA substrates typical of those generated at sites of DNA damage[2].
The C-terminal domain also contains a secondary RAD51-interaction site distinct from the BRC repeats, positioned immediately adjacent to the DNA-binding domain[1][43]. This C-terminal RAD51-binding motif is subject to cell cycle-dependent phosphorylation at serine 3291 by cyclin A-CDK2 and cyclin B-CDK1, a modification that blocks the interaction between BRCA2 and RAD51 during interphase and early mitosis when DNA repair via homologous recombination is not required[38][41]. Upon DNA damage, this phosphorylation is rapidly suppressed, allowing RAD51 recruitment to this domain and promoting DNA repair[38][41]. This represents a sophisticated regulatory mechanism in which cell cycle control and DNA damage sensing are integrated to ensure that recombination-mediated repair is restricted to appropriate phases of the cell cycle.
The extreme C-terminus of the BRCA2 protein contains three nuclear localization signals (NLS) that direct the protein to the cell nucleus and are essential for its biological function[1][7]. These NLS sequences are located at amino acid positions 3263-3269 (NLS1), 3311-3317 (NLS2), and 3381-3385 (NLS3), flanking the C-terminal RAD51-binding domain[1]. Only NLS1 is highly conserved across mammalian species, while NLS2 and NLS3 are less conserved, though all three are enriched in positively charged amino acid residues characteristic of classical nuclear localization signals[1]. The presence of multiple redundant NLS elements suggests functional importance, as defects in nuclear transport of BRCA2 resulting from mutations that disrupt these signals have been proposed as potential mechanisms of carcinogenesis in hereditary breast cancer patients[7]. The regulation of BRCA2 nuclear localization is not merely dependent on these intrinsic signals but is also controlled by its interaction with the DSS1 protein, which masks a nuclear export signal (NES) and thereby promotes nuclear accumulation[44].
The fundamental biological function of BRCA2 is to act as a recombination mediator—a molecular facilitator that orchestrates the recruitment and nucleation of RAD51 filaments onto single-stranded DNA substrates generated during homologous recombination-based repair of DNA double-strand breaks and interstrand crosslinks[1][8][31][43]. This mediator function addresses a critical biological problem: replication protein A (RPA), a highly abundant and stable single-strand DNA binding protein, rapidly occupies and sequester exposed ssDNA with extraordinary avidity, effectively shielding the DNA substrate from RAD51 access and creating a substantial kinetic barrier to filament assembly[8][31][34]. In the absence of an intervention, RAD51 cannot effectively displace RPA from ssDNA, and productive recombination cannot proceed. The BRCA2 protein solves this problem through a multi-step mechanism in which it physically interacts with both RAD51 (through its BRC repeats) and single-stranded DNA (through its C-terminal DNA-binding domain), positioning these two components in favorable spatial and energetic configurations that enable RAD51 nucleoprotein filament formation to occur efficiently despite RPA occupancy[34].
Recent high-resolution single-molecule studies have demonstrated that BRCA2 functions as a molecular chaperone for RAD51, actually delivering preassembled dimeric nuclei of RAD51 directly to RPA-coated ssDNA, thereby accelerating the otherwise rate-limiting nucleation step of filament assembly to rates approaching those observed on naked ssDNA devoid of RPA[34]. This chaperoning activity represents a remarkable molecular accomplishment, as it enables the nucleation of RAD51 filaments at a 6.3-fold increased frequency near the ssDNA-dsDNA junction compared to conditions without BRCA2[34]. Following nucleation, BRCA2 facilitates unidirectional 3' to 5' directional growth of the RAD51 filament, with BRCA2 molecules ultimately capping the 3' end of the filament to prevent inappropriate extension onto double-stranded DNA[2][37][42]. This capping function is particularly important because RAD51 filaments that extend onto dsDNA regions would be nonproductive for homologous pairing and would represent a waste of cellular resources.
The mechanism by which BRCA2 BRC repeats regulate RAD51 binding displays remarkable sophistication, operating through what has been termed a "conformational switch" mechanism in which the engagement of BRC repeats with RAD51 influences the ATP hydrolysis activity of RAD51 and its ability to bind different DNA substrates[8][31]. The BRC1-4 repeats, through their high-affinity interaction with RAD51 monomers, inhibit the DNA-dependent ATP hydrolysis of RAD51, thereby slowing the dissociation of RAD51 from ssDNA and promoting stable filament nucleation and early growth[8][31]. Simultaneously, these same repeats reduce the affinity of RAD51 for double-stranded DNA, creating a situation in which RAD51 loaded onto BRC repeats exhibits preference for ssDNA substrates and avoids wasteful interactions with the surrounding dsDNA duplex[8][31]. This selective promotion of RAD51 binding to ssDNA while inhibiting its binding to dsDNA represents an elegant solution to the problem of substrate specificity, ensuring that recombination machinery is directed toward the sites of DNA damage where single-stranded regions have been generated rather than being inappropriately loaded onto intact double-helical DNA.
The interaction between individual BRC repeats and RAD51 is not static but displays remarkable plasticity depending on the nucleotide state and assembly status of RAD51[16][34]. The BRC1-4 repeats bind with higher affinity to free RAD51 monomers and RAD51 oligomers that have not yet assembled on DNA, whereas the BRC5-8 repeats exhibit preference for RAD51 that is already engaged in nucleoprotein filaments[16]. This functional specialization suggests an evolutionary optimization in which different BRC repeats have been selected to participate in distinct stages of recombination-mediated repair, creating a system in which BRCA2 can dynamically regulate RAD51 loading, extension, and stabilization in a temporally coordinated fashion.
The process by which BRCA2 facilitates RAD51 filament formation appears to involve multiple rounds of nucleation followed by gap-filling rather than progressive elongation from a single nucleation site[2][37][42]. Three-dimensional electron microscopy reconstructions have revealed that a BRCA2 dimer recruits two oppositely-oriented sets of RAD51 molecules, yet upon ssDNA binding, only one set of RAD51 can productively engage with the DNA due to the inherent polarity of the ssDNA substrate[2][37][42]. This architectural constraint creates a situation in which BRCA2 achieves efficiency through the formation of multiple nucleation clusters along the ssDNA length, each capable of nucleating RAD51 polymerization independently, with subsequent gap-filling to create a continuous filament[2]. This multi-site nucleation model explains how BRCA2 can efficiently overcome the kinetic barrier imposed by RPA despite the massive thermodynamic advantage RPA possesses in DNA binding.
The stimulation of RAD51-mediated DNA strand exchange is differentially regulated by the two classes of BRC repeats[16][43]. BRC1-4 repeats strongly stimulate RAD51-catalyzed strand exchange activity with an affinity-dependent relationship, in which BRC repeats with higher RAD51 binding affinity produce greater stimulation of strand exchange[16]. In contrast, BRC5-8 repeats, despite their ability to stabilize nascent RAD51-ssDNA filaments, do not substantially stimulate DNA strand exchange at the concentrations tested, suggesting their role is restricted to stabilization of already-assembled filaments rather than participation in the strand exchange catalysis itself[16]. This division of labor between BRC repeat classes appears functionally important for ensuring that nucleation and extension of RAD51 filaments are tightly coordinated with the subsequent strand exchange reaction that is essential for homologous recombination-mediated repair.
The BRCA2 protein does not function in isolation but rather as a central node in a broader network of recombination-associated proteins that coordinate all aspects of homologous recombination-mediated DNA repair[43]. At the upstream end, BRCA2 interacts directly with the PALB2 protein (Partner and Localizer of BRCA2) through its N-terminal region, and this interaction is essential for BRCA2 localization to sites of DNA damage following ionizing radiation or other DNA-damaging stresses[15][43][55]. PALB2 itself associates with BRCA1 through a coiled-coil domain interaction, creating a hierarchical assembly in which BRCA1 serves as an upstream regulator that promotes the accumulation of PALB2 and BRCA2 at DNA-damage foci[55]. The BRCA1-PALB2-BRCA2 axis thus represents an integrated checkpoint for DNA damage recognition and response, with PALB2 functioning as the essential linker connecting BRCA1's early DNA damage sensing functions to BRCA2's recombination mediator activities[55].
BRCA2's interaction with the acidic protein DSS1 represents another critical regulatory partnership[44][47][51]. DSS1 binds to the BRCA2 C-terminal DNA-binding domain and is required for the stability of BRCA2 in cells, with mutations that disrupt DSS1 binding resulting in reduced protein levels and cellular dysfunction[44][47]. Beyond its stabilizing role, DSS1 appears to serve regulatory functions, including antagonizing multimerization of BRCA2 and promoting the monomeric form of the protein, which may be preferentially active for certain cellular functions[51]. DSS1 also appears to facilitate the displacement of RPA by RAD51 during homologous recombination by reducing RPA's affinity for ssDNA, providing another mechanism through which BRCA2-associated proteins enhance recombination efficiency[44].
Beyond its well-established roles in double-strand break repair, BRCA2 participates in the Fanconi anemia (FA) DNA repair pathway that is specifically responsible for repair of interstrand crosslinks (ICLs)[9][19][22][43]. In this pathway, BRCA2 functions as FANCD1, the protein product of the FANCB2 gene in the Fanconi anemia complementation group, and participates in the downstream steps of ICL repair after initial nucleolytic unhooking of the lesion[9][19][22]. The role of BRCA2 in ICL repair involves its mediator function in directing RAD51 to sites of stalled replication forks where ICLs have been encountered, and importantly, recent evidence indicates that BRCA2 participates in protecting the DNA at ICL sites from inappropriate degradation by the DNA2 nuclease-WRN helicase complex[9][22]. This protection function appears to be distinct from BRCA2's role in protecting hydroxyurea-stalled replication forks, as indicated by studies of BRCA2 DNA-binding domain mutants discovered in Fanconi anemia patients that display loss of replication fork protection but only moderate deficiency in homologous recombination repair[9].
In addition to its established role as a mediator of homologous recombination, BRCA2 functions in protecting stalled replication forks from nucleolytic degradation, a process essential for maintaining genome stability when replication machinery encounters DNA damage or other obstacles that require transient fork arrest[9][43]. When DNA replication forks encounter obstacles such as interstrand crosslinks or are stalled by hydroxyurea treatment (which depletes dNTP pools), the exposed single-stranded DNA at these forks becomes vulnerable to attack by nucleolytic enzymes, particularly the MRE11 nuclease component of the MRE11-RAD50-NBS1 (MRN) complex[9][43]. BRCA2, working in concert with RAD51, protects these stalled replication forks by mechanisms that appear to prevent or limit the access of MRE11 to the replication fork, thereby preserving the integrity of the nascent DNA strand and maintaining the structural information required for subsequent fork restart[9][43].
The precise molecular mechanism by which BRCA2 and RAD51 protect replication forks from MRE11-dependent degradation remains incompletely understood, but appears to involve the formation of a protective nucleoprotein structure at the fork, possibly involving RAD51 filament assembly at the single-stranded DNA regions exposed at stalled forks[9]. This fork protection function has been shown to require the RAD51-interaction domains of BRCA2 but to be largely independent of the C-terminal DNA-binding domain, suggesting that the critical function involves BRCA2's ability to deliver RAD51 to fork sites rather than direct DNA binding by BRCA2 itself[9]. Notably, cells expressing BRCA2 mutations that substantially impair replication fork protection may retain near-normal homologous recombination repair capability, indicating that these two functions can be genetically separated and may involve distinct structural or mechanistic aspects of BRCA2's interactions with RAD51 and DNA[9].
Recent research has revealed that BRCA2 participates in at least two mechanistically distinct replication fork protection processes, distinguished by the nature of the stalling agent and the specific nuclease that threatens fork integrity[9]. At hydroxyurea-induced stalled forks, BRCA2 and RAD51 work together to protect nascent DNA from MRE11-dependent exonucleolytic degradation, as evidenced by the fact that MRE11 inhibition or depletion rescues the nuclease sensitivity of BRCA2-deficient cells[9]. In contrast, at interstrand crosslink-induced stalled forks, BRCA2 protection operates through a mechanism that guards against degradation by the DNA2 nuclease-WRN helicase complex rather than MRE11[9]. This functional dichotomy suggests evolutionary optimization in which BRCA2 has been selected to respond to the specific nucleolytic threats posed by different types of replication stress, possibly through distinct protein-protein interactions or RAD51 assembly configurations that are specialized for each context.
BRCA2 functions exclusively within the cell nucleus, where it localizes to discrete foci at sites of DNA damage in response to ionizing radiation or other genotoxic stress[10][45]. The protein is expressed in response to cell proliferation, with expression initiated before DNA synthesis, consistent with a role in preparing cells for replication-associated DNA damage responses[10][45]. Cell cycle analysis has revealed that BRCA2 mRNA expression is regulated tightly by the cell cycle, with maximum mRNA levels observed in late G1 and S phase, substantially lower levels in G0 and early G1, and moderate levels in G2/M[56][59]. This cell cycle-regulated expression pattern suggests that cellular BRCA2 activity is heightened precisely during the phases when DNA replication occurs and when homologous recombination-mediated repair is most active, providing a temporal coordination between DNA damage susceptibility and DNA repair capacity.
The subcellular localization of BRCA2 is not confined to nucleoplasm but includes dynamic association with additional cellular structures during specific phases of the cell cycle[26][29]. During interphase, BRCA2 localizes diffusely throughout the nucleus and concentrates in nuclear foci at sites of DNA damage[26]. During mitosis, BRCA2 associates with centrosomes, the spindle midzone, and the cytokinetic midbody, suggesting functions beyond canonical DNA repair[26][29]. At the midbody during abscission, BRCA2 localizes through interaction with the actin-binding protein Filamin A, and recruits endosomal sorting complex required for transport (ESCRT) proteins including Alix and Tsg101, participating in the final stages of cell division[29]. This extrarepair localization of BRCA2 and its association with cytokinesis machinery indicates that the protein participates in cellular processes beyond DNA damage response, suggesting a broader role in maintaining cell integrity through multiple stress conditions.
The nuclear import of BRCA2 is mediated through recognition of its three C-terminal nuclear localization signals by the classical nuclear import machinery involving importin-α and importin-β[1][7]. However, the regulation of BRCA2 nuclear accumulation extends beyond these intrinsic targeting signals to include control through interaction with DSS1, which masks a nuclear export signal (NES) that would otherwise promote nuclear export[44]. When DSS1 is bound to BRCA2, the protein accumulates in the nucleus with high efficiency, whereas variants of BRCA2 that fail to bind DSS1 effectively show reduced nuclear localization and accumulation in the cytoplasm[44]. This DSS1-dependent control of BRCA2 localization provides an additional layer of regulation in which the stability and activity of BRCA2 in the nucleus are linked to its interaction with a critical partner protein, ensuring that the protein remains in the compartment where DNA repair functions must occur.
The activity of BRCA2 in promoting homologous recombination is subject to sophisticated cell cycle-dependent regulation mediated by phosphorylation of a critical serine residue (Ser3291) in the C-terminal RAD51-binding domain[38][41]. During interphase, particularly in G2/M phase, cyclin A-CDK2 and cyclin B-CDK1 phosphorylate BRCA2 at Ser3291, a modification that blocks the interaction between BRCA2 and RAD51 through this C-terminal domain and suppresses homologous recombination repair[38][41]. This phosphorylation-mediated suppression of RAD51 binding appears to function as a checkpoint control mechanism that ensures homologous recombination is not activated at inappropriate times in the cell cycle when it might generate chromosomal rearrangements or other genomic instability.
Upon DNA damage, this phosphorylation is rapidly suppressed through a mechanism involving the degradation of CDC25A phosphatase, which maintains CDK2 activity[38]. The reduction in Ser3291 phosphorylation following DNA damage allows RAD51 to bind to the C-terminal domain of BRCA2, facilitating recruitment of RAD51 to damage sites and activating homologous recombination-mediated repair[38]. Interestingly, cyclin D1, which activates CDK4/6 in early G1, prevents the phosphorylation of BRCA2 Ser3291 by competing with cyclin A and cyclin B for binding to BRCA2, thereby maintaining the C-terminal RAD51-binding domain in a dephosphorylated, active state during the G1/S transition[38]. This intricate regulatory network ensures that the balance between suppression and activation of BRCA2-dependent homologous recombination is maintained by multiple cell cycle checkpoints and is responsive to both cell cycle phase and DNA damage signals.
Beyond its role as a mediator of homologous recombination, BRCA2 participates in the G2/M DNA damage checkpoint that arrests cells in G2 phase following DNA damage to prevent segregation of damaged chromosomes and maintain genome stability[1][20][23]. The BRCA1-PALB2-BRCA2 axis is essential for this checkpoint control, with BRCA1 playing a prominent role in both checkpoint activation and maintenance, while BRCA2 and PALB2 function particularly in checkpoint maintenance[20]. Interestingly, the G2/M checkpoint function of BRCA2 appears to operate through a mechanism distinct from its homologous recombination mediator function, as the checkpoint response is independent of CHK1 and CHK2 kinase phosphorylation, the apical kinases typically responsible for checkpoint control[20]. This suggests that BRCA2 participates in an alternative checkpoint signaling pathway that may operate through its interactions with PALB2 and other checkpoint-associated proteins.
Beyond its established roles in somatic cell homologous recombination, BRCA2 participates in meiotic recombination by functioning as a mediator of the meiosis-specific recombinase DMC1 (disrupted meiotic cDNA 1), a paralog of RAD51[25][28]. The interaction between BRCA2 and DMC1 maps to a domain in the central region of BRCA2 (approximately residues 2386-2411) that is distinct from the BRC repeats that mediate RAD51 interaction, indicating that BRCA2 possesses separate domains for binding and regulating the two recombinases[25]. This primary DMC1 interaction domain is highly conserved in mammalian BRCA2 proteins but is notably absent in BRCA2 orthologs from plants and invertebrates such as Arabidopsis and Caenorhabditis elegans, suggesting that the meiotic function of mammalian BRCA2 represents a derived characteristic that may enhance meiotic fidelity in complex organisms[25].
The BRC repeats also interact with DMC1, but with different affinities than with RAD51, suggesting that the same BRC repeat domains can participate in regulating both the somatic and meiotic recombinases[28]. Biochemically, BRCA2 stimulates DMC1-catalyzed DNA strand exchange activity through mechanisms similar to those employed for RAD51 stimulation, providing evidence that BRCA2 functions as a universal regulator of RAD51/DMC1 recombinase actions[25]. The physiological importance of BRCA2's meiotic function is underscored by the infertility phenotype of BRCA2-deficient mice, in which spermatocytes fail to progress beyond early prophase I of meiosis and oocytes display high frequencies of nuclear abnormalities[53].
BRCA2 exists in cells in multiple oligomeric states, including both monomeric and dimeric forms, with the proportions of these states being regulated by binding to partner proteins and single-stranded DNA[51][54]. Biochemical and electron microscopic analysis has revealed that BRCA2 multimerization is counteracted by both DSS1 and ssDNA, which promote stabilization of monomeric forms of the protein[51]. The multimerization of BRCA2 involves self-interactions between the N- and C-terminal regions of the protein, which can be disrupted by DSS1 binding to the DNA-binding domain and by ssDNA engagement with the DNA-binding regions[51]. The functional significance of these different oligomeric states remains incompletely understood, though evidence suggests that the monomeric and oligomeric forms of BRCA2 may be differentially active for different cellular functions in recombinational DNA repair and replication fork stabilization[51].
The conformational flexibility of BRCA2 represents a remarkable molecular feature, with the N- and C-terminal regions identified as particularly flexible regions that significantly influence BRCA2 oligomerization and its interactions with binding partners[54]. Purified BRCA2 displays substantial rearrangements in its molecular architecture in response to binding with RAD51 and ssDNA, structural changes that are consistent with the protein containing intrinsically disordered regions[39]. This conformational plasticity may be important for BRCA2's ability to accommodate the binding of multiple partner proteins and to undergo the structural transitions necessary for its participation in the various stages of homologous recombination, from initial RAD51 nucleation through strand invasion and beyond.
The integration of BRCA2 into a functional complex with BRCA1 and PALB2 represents a critical aspect of its cellular function, with PALB2 serving as the essential linker that directly associates with both proteins[15][55]. PALB2 contains an N-terminal coiled-coil domain that interacts directly with a coiled-coil motif in BRCA1, and a C-terminal WD40 domain that binds the N-terminus of BRCA2[15][55]. The formation of the BRCA1-PALB2-BRCA2 complex appears essential for localizing both PALB2 and BRCA2 to sites of DNA damage, as BRCA1 serves as an upstream regulator that promotes the accumulation of both PALB2 and BRCA2 at ionizing radiation-induced foci[55]. This hierarchical organization suggests that BRCA1 acts as a damage sensor that recruits the PALB2-BRCA2 recombination machinery to damage sites, with PALB2 functioning as an adaptor that bridges the two proteins and coordinates their activities.
Beyond its linker function, PALB2 contributes its own biochemical activities to the complex, including direct binding and stabilization of RAD51 filaments, promotion of strand invasion, and reduction of RPA-mediated inhibition of recombination[15]. The recruitment of PALB2 to DNA damage foci requires interaction with BRCA1, but the assembly of PALB2 nuclear foci is also promoted by additional factors including MDC1, RNF8, UIMC1 (RAP80), ABRAXAS, and RNF168, all proteins involved in BRCA1 recruitment, indicating that the assembly of the BRCA1-PALB2-BRCA2 complex is driven by multiple checkpoint signaling pathways[15]. This multi-layered recruitment mechanism suggests that the formation of this complex at DNA damage sites is a highly regulated process responsive to multiple forms of DNA damage and stress signals.
Heterozygous germline mutations in BRCA2 confer profound predisposition to breast, ovarian, pancreatic, prostate, and other malignancies, establishing BRCA2 as a classical tumor suppressor gene in which loss of function drives malignant transformation[1][3][49]. Women who inherit pathogenic BRCA2 variants have a lifetime risk of developing breast cancer exceeding 60%, substantially higher than the approximately 13% risk in the general population, and a lifetime ovarian cancer risk of approximately 13-29% compared to 1.1% in the general population[49]. The cancer predisposition associated with BRCA2 mutations follows the classic two-hit model of tumor suppression, in which the inherited heterozygous mutation in one allele is typically not sufficient to transform cells, but when combined with somatic loss of the remaining wild-type allele through deletion, point mutation, or epigenetic silencing, homozygous or compound deficiency results in genome instability, loss of checkpoint control, and malignant transformation[1][3].
The relationship between BRCA2 mutation location and cancer risk has been examined in multiple studies, with evidence suggesting that some structural domains may be associated with differential cancer predisposition phenotypes, though this remains an area of active investigation[46]. Breast cancers developing in BRCA2 mutation carriers exhibit distinct biological characteristics, including elevated frequencies of hormone receptor expression (particularly estrogen receptor positivity in a subset of BRCA2 carriers) in contrast to BRCA1-associated breast cancers which show higher frequencies of triple-negative phenotypes[49]. Male BRCA2 carriers show substantially elevated breast cancer risk (lifetime risk approximately 5-6%) compared to the general male population (approximately 0.1%), a recognition that has important implications for genetic screening and surveillance of male family members of BRCA2 mutation carriers[49].
Individuals who inherit pathogenic BRCA2 variants in both alleles (biallelic mutations) develop Fanconi anemia, a rare inherited disorder characterized by congenital abnormalities, chromosome fragility, progressive bone marrow failure, and substantially elevated cancer predisposition, particularly to leukemia and solid tumors, often presenting in childhood[3][19][22]. The severity of the Fanconi anemia phenotype typically exceeds that of heterozygous BRCA2 mutation carriers, reflecting the more severe compromise in DNA repair and genome stability that results from complete loss of BRCA2 function. This distinction between monoallelic and biallelic BRCA2 mutations highlights the critical importance of BRCA2 in maintaining genome stability and demonstrates the dose-dependent effects of BRCA2 deficiency on cancer predisposition.
The discovery that BRCA2-deficient cells exhibit synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibitors has revolutionized the therapeutic approach to BRCA2-associated malignancies[33][36]. PARP inhibitors block the base excision repair pathway by preventing PARP-catalyzed ADP-ribosylation of DNA damage response proteins, leading to accumulation of single-strand breaks in DNA[33][36]. In normal cells with functional BRCA2, these single-strand breaks are converted to double-strand breaks during DNA replication, but are then repaired through homologous recombination mediated by BRCA2-RAD51 complexes, allowing cells to survive[33][36]. However, in BRCA2-deficient cancer cells, the defective homologous recombination machinery cannot efficiently repair the accumulating DNA damage from PARP inhibition, resulting in excessive double-strand breaks and cell death[33][36].
Clinically, PARP inhibitors have shown substantial benefit in the treatment of BRCA1/2-mutant breast, ovarian, and pancreatic cancers, with FDA-approved agents including olaparib (Lynparza), which was the first PARP inhibitor approved and has demonstrated substantial clinical benefit[33][36]. The success of PARP inhibitor therapy in BRCA-deficient tumors exemplifies the power of precision medicine approaches in which detailed knowledge of molecular defects in cancer cells can be leveraged to design therapeutic strategies that selectively target cancer cells while minimizing effects on normal tissues[33]. However, resistance to PARP inhibitors can emerge through multiple mechanisms, including secondary BRCA2 mutations that restore protein function, alterations in replication fork protection pathways, and modulation of the homologous recombination machinery[33].
The development of PARP inhibitor resistance in BRCA2-mutant cancers has illuminated additional aspects of BRCA2 function and has revealed multiple pathways through which cancer cells can compensate for BRCA2 deficiency[33]. Secondary BRCA2 mutations that result in restoration of protein function represent the most common mechanism of resistance, occurring through frameshift-suppressing mutations that restore the open reading frame, or through mutations that convert stop codons to sense codons, allowing translation of full-length or nearly full-length protein[33]. This observation demonstrates that the catalytic function of BRCA2 in DNA repair is the critical target of synthetic lethality, and that restoration of even modest levels of BRCA2 activity can substantially enhance chemotherapy and PARP inhibitor resistance[33].
Understanding the molecular mechanisms by which BRCA2 exerts its tumor suppressor functions has revealed additional therapeutic opportunities beyond PARP inhibitors. DNA-damaging chemotherapy agents such as cisplatin remain highly effective in BRCA2-deficient tumors because they generate double-strand breaks that cannot be repaired efficiently through homologous recombination, making them synthetically lethal with BRCA2 deficiency through a mechanism similar to PARP inhibitors[49]. Emerging evidence suggests that targeting components of the DNA2-WRN complex that degrades stalled replication forks in BRCA2-deficient cells, or inhibiting components of the Fanconi anemia pathway, may provide additional therapeutic approaches in BRCA2-mutant malignancies[33][43].
The C-terminal DNA-binding domain of BRCA2 exhibits strong preference for single-stranded DNA compared to double-stranded DNA, a specificity that is critical for its function as a mediator of recombination-mediated DNA repair[2][34][37][42]. This preference appears to arise through the combined contributions of multiple OB folds that interact cooperatively with ssDNA, with OB2 and OB3 providing the primary binding interactions[2][14]. The binding of ssDNA to BRCA2 is not sequence-specific but rather length-dependent, with the protein requiring approximately 40 nucleotides for weak binding and more than 70 nucleotides for maximal affinity, suggesting that BRCA2 recognizes the extended single-stranded DNA regions characteristic of those generated during DNA damage processing[2][42].
The binding of ssDNA to the BRCA2 dimer involves an architectural arrangement in which the ssDNA binds along the long axis of the dimeric protein, positioned such that only one of the two oppositely-oriented sets of RAD51 molecules bound to the BRCA2 dimer can form productive contacts with the DNA[2][37][42]. This asymmetric arrangement appears mechanistically important for ensuring unidirectional growth of the RAD51 filament, with one end of the filament growing as RAD51 monomers are added, while the opposite end is capped by BRCA2, preventing extension in that direction[2][37][42]. Recent studies suggest that BRCA2 may preferentially engage at the 5' terminus of ssDNA-dsDNA junctions, though the protein does not show absolute preference for junction structures as do some orthologs such as the fungal Brh2 protein[31][34].
The interaction of BRCA2 with the small acidic protein DSS1 exerts substantial regulatory control over the DNA-binding activity of BRCA2, with DSS1 appearing to modulate the accessibility of DNA binding sites within the BRCA2 structure[44]. The DSS1 protein binds to the C-terminal DNA-binding domain of BRCA2, and this interaction both stabilizes the protein and influences its conformational state in ways that affect DNA binding[44]. Some evidence suggests that DSS1 acts as a negative modulator of DNA binding by BRCA2, occupying or blocking access to DNA-binding surfaces within the DNA-binding domain, thereby regulating the extent to which BRCA2 engages with DNA[44]. This regulatory mechanism provides another layer of control in which the DNA-binding activity of BRCA2 is not merely determined by intrinsic protein properties but is actively regulated by interaction with a partner protein, allowing cells to modulate the intensity of BRCA2-ssDNA interactions in response to cellular conditions.
The variant BRCA2 R2645G, identified in breast cancer patients and located near the DSS1 binding site, unexpectedly increases the ssDNA binding activity of BRCA2 while maintaining normal DSS1 binding, resulting in enhanced DNA recombination activity that paradoxically increases cancer susceptibility[44]. This observation demonstrates that optimal BRCA2 function requires tightly regulated ssDNA binding activity, and that enhancement of binding affinity beyond wild-type levels results in hyperrecombination phenotypes associated with chromosomal instability and increased cancer risk[44]. This finding illustrates a principle that tumor suppressor functions often require fine-tuned levels of activity, with both loss and gain of function potentially driving malignant transformation through distinct mechanisms.
The BRCA2 protein undergoes substantial conformational rearrangements in response to binding with its partner proteins RAD51 and ssDNA, changes that are believed to be important for the functional transitions required during homologous recombination[39][42]. Biochemical and biophysical studies employing atomic force microscopy and electron microscopy have documented that purified BRCA2 protein displays remarkable structural plasticity, with the protein adopting multiple conformations depending on its binding partners[39][54]. These conformational changes may serve important regulatory functions, allowing BRCA2 to transition between states optimized for RAD51 nucleation, filament extension, and strand invasion, with each stage of the recombination process potentially requiring distinct BRCA2 configurations.
The C-terminal and DNA-binding domains of BRCA2, despite being functionally distinct and separable by mutagenesis, appear to be structurally coupled, as deletions of one domain substantially impair the conformational rearrangements triggered by binding partners[39]. This coupling suggests that the overall three-dimensional architecture of BRCA2 is important for its ability to respond to signals from binding partners and to undergo the structural transitions necessary for its biochemical functions. The considerable flexibility of the N- and C-terminal regions of BRCA2 may allow these domains to sample multiple conformations, facilitating the protein's ability to accommodate different binding partners and substrates at different stages of the recombination process[54].
Recent evidence indicates that BRCA2 participates in transcriptional regulation through interaction with the estrogen receptor and involvement in the control of estrogen-responsive genes[27]. BRCA2 binds to the estrogen receptor upon estradiol treatment and interacts with proteins that regulate estrogen-dependent transcription, including the coactivator SRC-1[27]. Through these interactions, BRCA2 appears to suppress the transcriptional activation of the pS2 gene, a target gene of the estrogen receptor, suggesting a negative regulatory role of BRCA2 in estrogen-dependent transcription[27]. This novel function of BRCA2 beyond DNA repair may have implications for understanding the particular susceptibility of BRCA2 mutation carriers to hormone receptor-positive breast cancers and may suggest that some aspects of BRCA2 function in breast tissue are related to hormonal responsiveness rather than solely to DNA damage response.
The expression of BRCA2 is subject to post-transcriptional regulation through microRNA-mediated mechanisms, with miR-19a and miR-19b identified as negative regulators of BRCA2 mRNA expression[30]. These microRNAs target a response element in the 3' untranslated region of BRCA2 mRNA, and overexpression of miR-19a or miR-19b in multiple cell lines results in decreased BRCA2 mRNA and protein levels[30]. The extent of miRNA-mediated suppression appears to be cell-type dependent, with the greatest effects observed in pancreatic cancer cell lines, suggesting that miR-19a/b-mediated BRCA2 suppression may be particularly relevant in specific tissue contexts[30]. This microRNA-mediated regulation of BRCA2 expression suggests that dysregulation of miR-19a/b levels in tumors could contribute to reduced BRCA2 expression and consequent genomic instability, providing an alternative mechanism through which BRCA2 function could be compromised in cancers without somatic mutations in the BRCA2 gene itself.
The BRCA2 protein represents a remarkable molecular machine that integrates multiple functions essential for maintaining genomic stability across multiple cellular contexts including homologous recombination-mediated repair of double-strand breaks and interstrand crosslinks, protection of stalled replication forks, cell cycle checkpoint control, and meiotic recombination in germ cells[1][8][9][20][25][31]. The protein's large size and complex modular architecture enable it to serve as a central node in networks of protein-protein interactions that coordinate the activities of numerous DNA repair and checkpoint proteins, with distinct domains specialized for binding specific partners including RAD51, RAD51 (DMC1), PALB2, DSS1, and multiple other cellular proteins[1][15][25][43][55]. The cell cycle-regulated phosphorylation of BRCA2 and its dynamic localization to different cellular structures throughout the cell cycle indicate that BRCA2 activity is tightly coordinated with cellular proliferation and the specific requirements of different phases of the cell cycle[10][38][56].
The functional importance of BRCA2 in maintaining genome stability is underscored by the severe consequences of its inactivation, ranging from embryonic lethality in complete knockout organisms, to Fanconi anemia in humans with biallelic mutations, to dramatically elevated cancer predisposition in heterozygous carriers[1][3][50][53]. The discovery of synthetic lethality between BRCA2 deficiency and PARP inhibitors has provided powerful therapeutic tools for treating BRCA2-associated malignancies, though the emergence of resistance mechanisms has illuminated the multiple pathways through which cancer cells can compensate for BRCA2 loss[33]. Future advances in understanding BRCA2 function are likely to come from studies that integrate structural, biochemical, and cellular approaches to clarify the molecular mechanisms by which different BRCA2 domains and post-translational modifications regulate the protein's interactions with its diverse binding partners and substrates. Additionally, continued investigation of how BRCA2 integrates DNA damage responses with cell cycle control, replication fork dynamics, and transcriptional regulation may reveal additional aspects of this multifunctional protein's role in cancer prevention and identify new therapeutic opportunities for patients carrying BRCA2 mutations.
Exported on March 22, 2026 at 01:35 AM
Organism: Homo sapiens
Sequence:
MPIGSKERPTFFEIFKTRCNKADLGPISLNWFEELSSEAPPYNSEPAEESEHKNNNYEPNLFKTPQRKPSYNQLASTPIIFKEQGLTLPLYQSPVKELDKFKLDLGRNVPNSRHKSLRTVKTKMDQADDVSCPLLNSCLSESPVVLQCTHVTPQRDKSVVCGSLFHTPKFVKGRQTPKHISESLGAEVDPDMSWSSSLATPPTLSSTVLIVRNEEASETVFPHDTTANVKSYFSNHDESLKKNDRFIASVTDSENTNQREAASHGFGKTSGNSFKVNSCKDHIGKSMPNVLEDEVYETVVDTSEEDSFSLCFSKCRTKNLQKVRTSKTRKKIFHEANADECEKSKNQVKEKYSFVSEVEPNDTDPLDSNVANQKPFESGSDKISKEVVPSLACEWSQLTLSGLNGAQMEKIPLLHISSCDQNISEKDLLDTENKRKKDFLTSENSLPRISSLPKSEKPLNEETVVNKRDEEQHLESHTDCILAVKQAISGTSPVASSFQGIKKSIFRIRESPKETFNASFSGHMTDPNFKKETEASESGLEIHTVCSQKEDSLCPNLIDNGSWPATTTQNSVALKNAGLISTLKKKTNKFIYAIHDETSYKGKKIPKDQKSELINCSAQFEANAFEAPLTFANADSGLLHSSVKRSCSQNDSEEPTLSLTSSFGTILRKCSRNETCSNNTVISQDLDYKEAKCNKEKLQLFITPEADSLSCLQEGQCENDPKSKKVSDIKEEVLAAACHPVQHSKVEYSDTDFQSQKSLLYDHENASTLILTPTSKDVLSNLVMISRGKESYKMSDKLKGNNYESDVELTKNIPMEKNQDVCALNENYKNVELLPPEKYMRVASPSRKVQFNQNTNLRVIQKNQEETTSISKITVNPDSEELFSDNENNFVFQVANERNNLALGNTKELHETDLTCVNEPIFKNSTMVLYGDTGDKQATQVSIKKDLVYVLAEENKNSVKQHIKMTLGQDLKSDISLNIDKIPEKNNDYMNKWAGLLGPISNHSFGGSFRTASNKEIKLSEHNIKKSKMFFKDIEEQYPTSLACVEIVNTLALDNQKKLSKPQSINTVSAHLQSSVVVSDCKNSHITPQMLFSKQDFNSNHNLTPSQKAEITELSTILEESGSQFEFTQFRKPSYILQKSTFEVPENQMTILKTTSEECRDADLHVIMNAPSIGQVDSSKQFEGTVEIKRKFAGLLKNDCNKSASGYLTDENEVGFRGFYSAHGTKLNVSTEALQKAVKLFSDIENISEETSAEVHPISLSSSKCHDSVVSMFKIENHNDKTVSEKNNKCQLILQNNIEMTTGTFVEEITENYKRNTENEDNKYTAASRNSHNLEFDGSDSSKNDTVCIHKDETDLLFTDQHNICLKLSGQFMKEGNTQIKEDLSDLTFLEVAKAQEACHGNTSNKEQLTATKTEQNIKDFETSDTFFQTASGKNISVAKESFNKIVNFFDQKPEELHNFSLNSELHSDIRKNKMDILSYEETDIVKHKILKESVPVGTGNQLVTFQGQPERDEKIKEPTLLGFHTASGKKVKIAKESLDKVKNLFDEKEQGTSEITSFSHQWAKTLKYREACKDLELACETIEITAAPKCKEMQNSLNNDKNLVSIETVVPPKLLSDNLCRQTENLKTSKSIFLKVKVHENVEKETAKSPATCYTNQSPYSVIENSALAFYTSCSRKTSVSQTSLLEAKKWLREGIFDGQPERINTADYVGNYLYENNSNSTIAENDKNHLSEKQDTYLSNSSMSNSYSYHSDEVYNDSGYLSKNKLDSGIEPVLKNVEDQKNTSFSKVISNVKDANAYPQTVNEDICVEELVTSSSPCKNKNAAIKLSISNSNNFEVGPPAFRIASGKIVCVSHETIKKVKDIFTDSFSKVIKENNENKSKICQTKIMAGCYEALDDSEDILHNSLDNDECSTHSHKVFADIQSEEILQHNQNMSGLEKVSKISPCDVSLETSDICKCSIGKLHKSVSSANTCGIFSTASGKSVQVSDASLQNARQVF
I begin with the InterPro architecture. IPR015525 (Breast cancer type 2 susceptibility protein family, residues 1–2000) blankets the entire polypeptide, defining it as a BRCA2-class mediator of homologous recombination. Nested within this scaffold, IPR002093 (BRCA2 repeat, residues 1002–2000) marks a C-terminal array of BRCA2 BRC repeats. This repeat array forms a high-affinity docking platform for recombinase machinery—classically RAD51—and creates an avidity-driven assembly surface that nucleates recombination filaments. The N-to-C arrangement—an extensive BRCA2 core followed by a dense repeat cluster—causally dictates a mechanism: the N-terminal core stabilizes and regulates the platform, while the C-terminal repeats concentrate and organize recombinase complexes for strand invasion and exchange.
From this architecture, the molecular function resolves to a non-enzymatic, repeat-mediated assembly factor with strong protein-binding capacity. The BRC-repeat array and the BRCA2 family scaffold jointly enforce selective high-affinity interactions with recombinases and accessory mediators, establishing GO:0005515 protein binding as the operative molecular function.
These assemblies drive the biological process of homologous recombination, where DNA strand exchange restores intact chromatids. By concentrating and stabilizing RAD51-centered filaments and coordinating upstream end resection and downstream post-exchange steps, this architecture enacts GO:0006310 DNA recombination and thereby safeguards genome integrity during replication and repair.
Cellular localization follows from function and architecture. Homologous recombination occurs on chromatin within the nucleus, and BRCA2-family scaffolds shuttle to and concentrate in nuclear repair foci. Thus, the most parsimonious cellular component is GO:0005634 nucleus, consistent with a soluble nuclear assembly factor that accumulates at DNA damage sites.
Mechanistically, I hypothesize that the C-terminal BRCA2 repeats recruit and stabilize RAD51 assemblies, while the broader BRCA2 scaffold coordinates accessory factors that manage filament dynamics and handoff to downstream repair modules. Likely partners include recombinases and mediator complexes that load and stabilize RAD51 on single-stranded DNA; additional nuclear repair hubs may transiently engage topoisomerases and chromatin remodelers to complete recombination and restore chromosome integrity.
A nuclear DNA-repair assembly factor that safeguards genome stability by organizing homologous recombination. Its large scaffold organizes a C-terminal repeat array that concentrates recombinase machinery to build strand-exchange filaments, thereby promoting accurate repair and chromosome integrity. It operates within the nucleus, where it assembles and stabilizes recombination complexes to coordinate filament formation and downstream repair steps.
Involved in the homologous recombination repair (HRR) pathway of DNA repair thereby contributing to maintain genomic stability.
IPR015525, family) — residues 1-2000IPR002093, repeat) — residues 1002-2000Molecular Function: molecular_function (GO:0003674), catalytic activity (GO:0003824), binding (GO:0005488), organic cyclic compound binding (GO:0097159), heterocyclic compound binding (GO:1901363), transferase activity (GO:0016740), catalytic activity, acting on a protein (GO:0140096), protein binding (GO:0005515), identical protein binding (GO:0042802), cytoskeletal protein binding (GO:0008092), nucleic acid binding (GO:0003676), peptide-lysine-N-acetyltransferase activity (GO:0061733), acyltransferase activity (GO:0016746), enzyme binding (GO:0019899), histone acetyltransferase activity (GO:0004402), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747), protease binding (GO:0002020), tubulin binding (GO:0015631), DNA binding (GO:0003677), acetyltransferase activity (GO:0016407), gamma-tubulin binding (GO:0043015), histone H3 acetyltransferase activity (GO:0010484), histone H4 acetyltransferase activity (GO:0010485), N-acyltransferase activity (GO:0016410), single-stranded DNA binding (GO:0003697), N-acetyltransferase activity (GO:0008080), peptide N-acetyltransferase activity (GO:0034212)
Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), localization (GO:0051179), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), negative regulation of biological process (GO:0048519), response to abiotic stimulus (GO:0009628), cellular localization (GO:0051641), regulation of metabolic process (GO:0019222), cell cycle process (GO:0022402), nitrogen compound metabolic process (GO:0006807), cell cycle (GO:0007049), establishment of localization (GO:0051234), cellular component organization or biogenesis (GO:0071840), negative regulation of multicellular organismal process (GO:0051241), regulation of multicellular organismal process (GO:0051239), organic substance metabolic process (GO:0071704), macromolecule localization (GO:0033036), cellular metabolic process (GO:0044237), regulation of cellular process (GO:0050794), positive regulation of metabolic process (GO:0009893), cellular response to stimulus (GO:0051716), response to stress (GO:0006950), microtubule-based process (GO:0007017), negative regulation of cellular process (GO:0048523), primary metabolic process (GO:0044238), positive regulation of cellular process (GO:0048522), organonitrogen compound metabolic process (GO:1901564), mitotic cell cycle process (GO:1903047), positive regulation of macromolecule metabolic process (GO:0010604), response to radiation (GO:0009314), heterocycle metabolic process (GO:0046483), cell cycle DNA replication (GO:0044786), negative regulation of cell population proliferation (GO:0008285), protein metabolic process (GO:0019538), regulation of macromolecule metabolic process (GO:0060255), centrosome duplication (GO:0051298), microtubule cytoskeleton organization (GO:0000226), cellular aromatic compound metabolic process (GO:0006725), cellular nitrogen compound metabolic process (GO:0034641), macromolecule metabolic process (GO:0043170), positive regulation of biosynthetic process (GO:0009891), establishment of protein localization (GO:0045184), cellular response to environmental stimulus (GO:0104004), organic cyclic compound metabolic process (GO:1901360), regulation of cell population proliferation (GO:0042127), nucleobase-containing compound metabolic process (GO:0006139), positive regulation of cellular metabolic process (GO:0031325), cellular response to stress (GO:0033554), cellular response to abiotic stimulus (GO:0071214), regulation of biosynthetic process (GO:0009889), regulation of nitrogen compound metabolic process (GO:0051171), positive regulation of nitrogen compound metabolic process (GO:0051173), cellular macromolecule localization (GO:0070727), regulation of cellular metabolic process (GO:0031323), cellular component organization (GO:0016043), regulation of primary metabolic process (GO:0080090), microtubule organizing center organization (GO:0031023), cellular macromolecule metabolic process (GO:0044260), centrosome cycle (GO:0007098), mitotic cell cycle (GO:0000278), cellular response to radiation (GO:0071478), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to DNA damage stimulus (GO:0006974), nuclear DNA replication (GO:0033260), establishment of protein localization to organelle (GO:0072594), mitotic DNA replication (GO:1902969), regulation of epithelial cell proliferation (GO:0050678), regulation of gene expression (GO:0010468), protein modification process (GO:0036211), positive regulation of macromolecule biosynthetic process (GO:0010557), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), positive regulation of RNA metabolic process (GO:0051254), macromolecule modification (GO:0043412), negative regulation of epithelial cell proliferation (GO:0050680), nucleic acid metabolic process (GO:0090304), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), DNA metabolic process (GO:0006259), regulation of RNA metabolic process (GO:0051252), protein localization (GO:0008104), organelle organization (GO:0006996), response to ionizing radiation (GO:0010212), positive regulation of cellular biosynthetic process (GO:0031328), protein localization to organelle (GO:0033365), establishment of protein localization to chromosome (GO:0070199), cellular response to ionizing radiation (GO:0071479), regulation of RNA biosynthetic process (GO:2001141), DNA recombination (GO:0006310), regulation of DNA-templated transcription (GO:0006355), protein acylation (GO:0043543), peptidyl-amino acid modification (GO:0018193), DNA repair (GO:0006281), cytoskeleton organization (GO:0007010), regulation of mammary gland epithelial cell proliferation (GO:0033599), DNA-templated DNA replication maintenance of fidelity (GO:0045005), DNA replication (GO:0006260), positive regulation of RNA biosynthetic process (GO:1902680), histone modification (GO:0016570), protein localization to chromosome (GO:0034502), DNA-templated DNA replication (GO:0006261), positive regulation of DNA-templated transcription (GO:0045893), recombinational repair (GO:0000725), nucleotide-excision repair (GO:0006289), positive regulation of nucleic acid-templated transcription (GO:1903508), histone acetylation (GO:0016573), regulation of nucleic acid-templated transcription (GO:1903506), protein acetylation (GO:0006473), peptidyl-lysine modification (GO:0018205), replication fork processing (GO:0031297), double-strand break repair (GO:0006302), protein localization to chromosome, telomeric region (GO:0070198), double-strand break repair via homologous recombination (GO:0000724), histone H4 acetylation (GO:0043967), histone H3 acetylation (GO:0043966), peptidyl-lysine acetylation (GO:0018394), internal protein amino acid acetylation (GO:0006475), internal peptidyl-lysine acetylation (GO:0018393)
Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), microtubule organizing center (GO:0005815), synaptonemal structure (GO:0099086), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), membrane-enclosed lumen (GO:0031974), cytosol (GO:0005829), intracellular protein-containing complex (GO:0140535), chromosomal region (GO:0098687), catalytic complex (GO:1902494), nuclear protein-containing complex (GO:0140513), cytoplasm (GO:0005737), endomembrane system (GO:0012505), nucleoplasm (GO:0005654), lateral element (GO:0000800), secretory granule (GO:0030141), synaptonemal complex (GO:0000795), transferase complex (GO:1990234), cytoplasmic vesicle (GO:0031410), nuclear ubiquitin ligase complex (GO:0000152), intracellular organelle (GO:0043229), non-membrane-bounded organelle (GO:0043228), centrosome (GO:0005813), chromosome, telomeric region (GO:0000781), organelle lumen (GO:0043233), DNA repair complex (GO:1990391), ubiquitin ligase complex (GO:0000151), membrane-bounded organelle (GO:0043227), secretory vesicle (GO:0099503), intracellular membrane-bounded organelle (GO:0043231), intracellular non-membrane-bounded organelle (GO:0043232), vesicle (GO:0031982), intracellular organelle lumen (GO:0070013), intracellular vesicle (GO:0097708), nucleus (GO:0005634), cytoskeleton (GO:0005856), nuclear lumen (GO:0031981), chromosome (GO:0005694), nuclear chromosome (GO:0000228), microtubule cytoskeleton (GO:0015630), condensed chromosome (GO:0000793), condensed nuclear chromosome (GO:0000794)
Generated by BioReason
Source: BRCA2-bioreason-rl-predictions.md
The BioReason functional summary states:
A nuclear DNA-repair assembly factor that safeguards genome stability by organizing homologous recombination. Its large scaffold organizes a C-terminal repeat array that concentrates recombinase machinery to build strand-exchange filaments, thereby promoting accurate repair and chromosome integrity. It operates within the nucleus, where it assembles and stabilizes recombination complexes to coordinate filament formation and downstream repair steps.
This captures the core function of BRCA2 correctly. The identification of BRC repeats as a RAD51-binding platform and the role in homologous recombination (GO:0006310) are well-supported by the curated review, which lists double-strand break repair via homologous recombination (GO:0000724) as a core function. The nuclear localization is accurate.
However, the summary misses several important aspects. BRCA2 has a DNA-binding domain (the OB folds and tower domain at the C-terminus) that directly binds ssDNA -- this is not captured by the "non-enzymatic, repeat-mediated assembly factor" framing. The curated review includes single-stranded DNA binding (GO:0003697) as a function. Additionally, the predicted GO terms include acetyltransferase activities (histone H3/H4 acetyltransferase) which are incorrect for BRCA2 -- these appear to be prediction errors from the model.
The summary also omits BRCA2's role in replication fork protection and its interaction with PALB2, which mediates BRCA1-BRCA2 complex formation. The curated review addresses centrosome biology and gamma-tubulin binding, which BioReason does not capture.
Comparison with interpro2go:
The curated review does not list GO_REF:0000002 annotations prominently for BRCA2. BioReason's reasoning closely tracks what interpro2go would derive from IPR015525 (BRCA2 family) and IPR002093 (BRC repeat): protein binding and DNA recombination. The erroneous acetyltransferase predictions in BioReason's GO term list likely stem from model confusion rather than interpro2go mappings.
The trace correctly focuses on the BRC repeat array and BRCA2 family scaffold. The mechanistic hypothesis about RAD51 recruitment is accurate. The trace notes the absence of enzymatic domains, which is correct -- BRCA2 is a scaffold rather than a catalyst.
id: P51587
gene_symbol: BRCA2
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
BRCA2 (Breast cancer type 2 susceptibility protein) is a critical tumor suppressor
that functions
as a mediator of homologous recombination (HR) DNA repair. The protein contains
multiple functional
domains: BRC repeats that bind RAD51 recombinase, a DNA-binding domain (DBD) with
OB folds and tower
domain that binds ssDNA, and a C-terminal recombinase-binding region (CTRB) that
engages both DNA
and RAD51. BRCA2 loads and stabilizes RAD51 onto RPA-coated single-stranded DNA
to form the
presynaptic filament required for strand invasion during HR. Additionally, BRCA2
protects stalled
and reversed replication forks from MRE11-mediated nucleolytic degradation, a function
genetically
separable from but coordinated with HR. Key partners include RAD51, PALB2, BRCA1-BARD1,
and DSS1.
Loss of BRCA2 function causes homologous recombination deficiency (HRD), conferring
sensitivity to
PARP inhibitors and platinum agents. Biallelic mutations cause Fanconi anemia (complementation
group D1/FANCD1). BRCA2 localizes predominantly to the nucleus at DNA damage sites.
existing_annotations:
# === CORE MOLECULAR FUNCTION: ssDNA binding ===
- term:
id: GO:0003697
label: single-stranded DNA binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: BRCA2 binds single-stranded DNA through its DNA-binding domain (DBD)
containing OB folds and through its C-terminal region (CTRB). This is essential
for its function in loading RAD51 onto ssDNA during homologous recombination.
action: ACCEPT
reason: Core molecular function. The DBD with OB folds directly binds ssDNA to
facilitate RAD51 loading. This is well-supported by structural and biochemical
studies (PMID:20729832, Kwon et al. 2023 Nature Comm).
supported_by:
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "The canonical DBD comprises a helical domain (HD), three OB\
\ folds (OB1-OB3), and a tower domain appendage. It binds DNA with high affinity\
\ and preferentially engages ssDNA in concert with DSS1"
- reference_id: PMID:20729832
supporting_text: "Purified human BRCA2 stimulates RAD51-mediated recombination"
# === CORE BIOLOGICAL PROCESS: HR repair ===
- term:
id: GO:0000724
label: double-strand break repair via homologous recombination
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: BRCA2 is the central mediator of homologous recombination repair, loading
RAD51 onto resected ssDNA to form the presynaptic filament required for strand
invasion.
action: ACCEPT
reason: Core biological process. BRCA2's primary function is mediating HR by facilitating
RAD51 nucleoprotein filament formation. This is the defining function of BRCA2
and is well-established across multiple lines of evidence.
supported_by:
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "BRCA2 is a genome maintenance factor that mediates homologous\
\ recombination (HR) by loading and stabilizing the recombinase RAD51 on resected\
\ single-stranded DNA (ssDNA) to form the presynaptic filament required for\
\ homology search and strand exchange"
- term:
id: GO:0000724
label: double-strand break repair via homologous recombination
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Computational annotation consistent with BRCA2's established role in
HR repair.
action: ACCEPT
reason: This IEA annotation is correctly capturing BRCA2's core function in HR
repair. Redundant with IBA but valid.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: BRCA2 binds DNA through its DNA-binding domain containing OB folds. This
is a parent term of ssDNA binding.
action: ACCEPT
reason: Valid but less specific than GO:0003697 (ssDNA binding). BRCA2 does bind
DNA through its DBD and CTRB regions.
- term:
id: GO:0006281
label: DNA repair
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: BRCA2 functions in DNA repair, specifically homologous recombination
repair.
action: ACCEPT
reason: Valid parent term of the more specific GO:0000724. BRCA2 is fundamentally
a DNA repair protein.
# === PROTEIN BINDING - REMOVE (uninformative) ===
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10373512
review:
summary: This paper describes the interaction between BRCA2 and DSS1 (SEM1), a
functionally conserved protein. DSS1 binding is important for BRCA2 stability
and function.
action: REMOVE
reason: Generic protein binding is uninformative. The specific interaction (BRCA2-DSS1)
is important but should be annotated with a more specific term if available.
supported_by:
- reference_id: PMID:10373512
supporting_text: Interaction between the product of the breast cancer susceptibility
gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10551859
review:
summary: Paper describes BRC repeats binding to RAD51 and disruption of this interaction
leading to radiation hypersensitivity.
action: REMOVE
reason: Generic protein binding is uninformative. The functionally relevant interaction
is RAD51 binding via BRC repeats.
supported_by:
- reference_id: PMID:10551859
supporting_text: Expression of BRC repeats in breast cancer cells disrupts the
BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M
checkpoint control.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12442171
review:
summary: Structural study of RAD51-BRCA2 complex revealing molecular basis of
their interaction.
action: REMOVE
reason: Generic protein binding is uninformative. This important structural work
reveals RAD51 binding mechanism.
supported_by:
- reference_id: PMID:12442171
supporting_text: Insights into DNA recombination from the structure of a RAD51-BRCA2
complex.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15115758
review:
summary: Paper describes direct interaction between FANCD2 and BRCA2 in DNA damage
response.
action: REMOVE
reason: Generic protein binding is uninformative. FANCD2 interaction is relevant
to Fanconi anemia pathway.
supported_by:
- reference_id: PMID:15115758
supporting_text: Apr 28. Direct interaction of FANCD2 with BRCA2 in DNA damage
response pathways.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15800615
review:
summary: CDK-dependent phosphorylation of BRCA2 regulates RAD51 binding and recombinational
repair.
action: REMOVE
reason: Generic protein binding is uninformative. The key finding is regulated
RAD51 interaction.
supported_by:
- reference_id: PMID:15800615
supporting_text: CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism
for recombinational repair.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16205630
review:
summary: DSS1 is required for BRCA2 stability.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:16205630
supporting_text: DSS1 is required for the stability of BRCA2.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17420451
review:
summary: Analysis of PALB2/FANCN-associated breast cancer families, describing
PALB2 interaction.
action: REMOVE
reason: Generic protein binding is uninformative. PALB2 interaction is critical
for BRCA2 function.
supported_by:
- reference_id: PMID:17420451
supporting_text: Analysis of PALB2/FANCN-associated breast cancer families.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17515903
review:
summary: Interaction with BRCA2 C terminus protects RAD51-DNA filaments from BRC
repeat-mediated disassembly.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:17515903
supporting_text: Interaction with the BRCA2 C terminus protects RAD51-DNA filaments
from disassembly by BRC repeats.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17515904
review:
summary: Stabilization of RAD51 nucleoprotein filaments by BRCA2 C-terminal region.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:17515904
supporting_text: May 21. Stabilization of RAD51 nucleoprotein filaments by the
C-terminal region of BRCA2.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17541404
review:
summary: Interactions between BRCA2 and meiosis-specific recombinase DMC1.
action: REMOVE
reason: Generic protein binding is uninformative. DMC1 binding is relevant for
meiotic recombination.
supported_by:
- reference_id: PMID:17541404
supporting_text: May 31. Interactions between human BRCA2 protein and the meiosis-specific
recombinase DMC1.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18212739
review:
summary: FANCG promotes formation of complex containing BRCA2, FANCD2 and XRCC3.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:18212739
supporting_text: Jan 21. FANCG promotes formation of a newly identified protein
complex containing BRCA2, FANCD2 and XRCC3.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18264088
review:
summary: Resistance to therapy caused by intragenic deletion in BRCA2.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:18264088
supporting_text: Resistance to therapy caused by intragenic deletion in BRCA2.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19303847
review:
summary: BRC repeats modulate DNA-binding selectivity of RAD51.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:19303847
supporting_text: The BRC repeats of BRCA2 modulate the DNA-binding selectivity
of RAD51.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19369211
review:
summary: PALB2 is integral component of BRCA complex required for HR repair. With
BRCA1 and PALB2.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:19369211
supporting_text: PALB2 is an integral component of the BRCA complex required
for homologous recombination repair.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19609323
review:
summary: Structural basis for BRCA2 recruitment by PALB2.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:19609323
supporting_text: Structural basis for recruitment of BRCA2 by PALB2.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19628690
review:
summary: BRC repeats differentially regulate RAD51 binding on ssDNA vs dsDNA.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:19628690
supporting_text: The BRC repeats of human BRCA2 differentially regulate RAD51
binding on single- versus double-stranded DNA to stimulate strand exchange.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20421506
review:
summary: Physical and functional interactions between p53 and BRCA2.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:20421506
supporting_text: Mapping the physical and functional interactions between the
tumor suppressors p53 and BRCA2.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20729832
review:
summary: Purified BRCA2 stimulates RAD51-mediated recombination. Key mechanistic
study.
action: REMOVE
reason: Generic protein binding is uninformative. The important finding is RAD51
regulation.
supported_by:
- reference_id: PMID:20729832
supporting_text: Purified human BRCA2 stimulates RAD51-mediated recombination.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20729859
review:
summary: BRCA2 promotes RAD51 filament formation on RPA-covered ssDNA.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:20729859
supporting_text: Aug 22. Human BRCA2 protein promotes RAD51 filament formation
on RPA-covered single-stranded DNA.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21399666
review:
summary: HMG20b interaction with BRC repeats of BRCA2 has mitotic function.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:21399666
supporting_text: A mitotic function for the high-mobility group protein HMG20b
regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21601571
review:
summary: Valine 1532 of BRC repeat 4 important for BRCA2-RAD51 interaction.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:21601571
supporting_text: Epub 2011 May 17. Valine 1532 of human BRC repeat 4 plays an
important role in the interaction between BRCA2 and RAD51.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22116401
review:
summary: Synaptonemal complex protein SYCP3 impairs mitotic recombination by interfering
with BRCA2.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:22116401
supporting_text: Synaptonemal complex protein SYCP3 impairs mitotic recombination
by interfering with BRCA2.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22193777
review:
summary: ChAM motif mediates PALB2 chromatin binding and facilitates DNA repair.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:22193777
supporting_text: ChAM, a novel motif that mediates PALB2 intrinsic chromatin
binding and facilitates DNA repair.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22293751
review:
summary: APRIN is cell cycle specific BRCA2-interacting protein required for genome
integrity.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:22293751
supporting_text: APRIN is a cell cycle specific BRCA2-interacting protein required
for genome integrity and a predictor of outcome after chemotherapy in breast
cancer.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24013206
review:
summary: Cancer-associated BRCA2 mutation reveals masked nuclear export signals.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:24013206
supporting_text: Sep 8. A cancer-associated BRCA2 mutation reveals masked nuclear
export signals controlling localization.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24141787
review:
summary: PALB2 WD40 domain directly binds RAD51C, RAD51 and BRCA2.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:24141787
supporting_text: Breast cancer-associated missense mutants of the PALB2 WD40
domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24485656
review:
summary: PALB2 and BRCA2 stimulate polymerase eta at blocked replication forks.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:24485656
supporting_text: 2014 Jan 30. Breast cancer proteins PALB2 and BRCA2 stimulate
polymerase η in recombination-associated DNA synthesis at blocked replication
forks.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24981860
review:
summary: Human chromatin-related protein interactions.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:24981860
supporting_text: 2014 Jun 26. Human-chromatin-related protein interactions identify
a demethylase complex required for chromosome segregation.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25282148
review:
summary: Structure and mechanism of action of BRCA2 breast cancer tumor suppressor.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:25282148
supporting_text: 2014 Oct 5. Structure and mechanism of action of the BRCA2
breast cancer tumor suppressor.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28319063
review:
summary: Compromised BRCA1-PALB2 interaction associated with breast cancer risk.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:28319063
supporting_text: Mar 20. Compromised BRCA1-PALB2 interaction is associated with
breast cancer risk.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:30410870
review:
summary: Two missense variants preventing BRCA2-PALB2 interaction.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:30410870
supporting_text: Two Missense Variants Detected in Breast Cancer Probands Preventing
BRCA2-PALB2 Protein Interaction.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Dual proteome-scale networks reveal cell-specific remodeling of human
interactome.
action: REMOVE
reason: Generic protein binding is uninformative. High-throughput study.
supported_by:
- reference_id: PMID:33961781
supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific
remodeling of the human interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:34591612
review:
summary: Protein interaction landscape of breast cancer.
action: REMOVE
reason: Generic protein binding is uninformative. High-throughput study.
supported_by:
- reference_id: PMID:34591612
supporting_text: Oct 1. A protein interaction landscape of breast cancer.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:39009827
review:
summary: Proteome-scale characterisation of motif-based interactome rewiring by
disease mutations.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:39009827
supporting_text: 2024 Jul 15. Proteome-scale characterisation of motif-based
interactome rewiring by disease mutations.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9560268
review:
summary: BRC repeats critical for RAD51 binding and resistance to methyl methanesulfonate.
action: REMOVE
reason: Generic protein binding is uninformative. The important finding is RAD51
binding via BRC repeats.
# === IDENTICAL PROTEIN BINDING ===
supported_by:
- reference_id: PMID:9560268
supporting_text: The BRC repeats in BRCA2 are critical for RAD51 binding and
resistance to methyl methanesulfonate treatment.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:21601571
review:
summary: BRCA2 can form homodimers or oligomers.
action: KEEP_AS_NON_CORE
reason: BRCA2 oligomerization has been reported but is not central to its primary
function in HR repair.
supported_by:
- reference_id: PMID:21601571
supporting_text: Epub 2011 May 17. Valine 1532 of human BRC repeat 4 plays an
important role in the interaction between BRCA2 and RAD51.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:25282148
review:
summary: BRCA2 homodimerization.
action: KEEP_AS_NON_CORE
reason: Oligomerization is a secondary property, not core function.
# === IEA ANNOTATIONS FROM ORTHOLOG TRANSFER (GO_REF:0000107) ===
supported_by:
- reference_id: PMID:25282148
supporting_text: 2014 Oct 5. Structure and mechanism of action of the BRCA2
breast cancer tumor suppressor.
- term:
id: GO:0000722
label: telomere maintenance via recombination
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 has been shown to localize to telomeres and facilitate telomere
replication and capping through RAD51 loading (PMID:21076401).
action: KEEP_AS_NON_CORE
reason: BRCA2 does function at telomeres via its general HR function, but this
is not the primary cellular role. Supported by PMID:21076401.
- term:
id: GO:0001556
label: oocyte maturation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Developmental process in which oocytes develop. BRCA2 is required for
proper meiotic recombination.
action: KEEP_AS_NON_CORE
reason: Downstream developmental consequence of BRCA2's role in meiotic HR. Not
a direct molecular function.
- term:
id: GO:0001833
label: inner cell mass cell proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Embryonic developmental process. BRCA2 knockout is embryonic lethal.
action: MARK_AS_OVER_ANNOTATED
reason: This is a distal phenotypic consequence of loss of genome maintenance,
not a specific function of BRCA2.
- term:
id: GO:0006302
label: double-strand break repair
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Parent term of HR repair. BRCA2 specifically functions in HR, not NHEJ.
action: ACCEPT
reason: Valid parent term. BRCA2 functions specifically in the HR subtype of DSB
repair.
- term:
id: GO:0007283
label: spermatogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 is required for meiotic recombination during spermatogenesis. HSF2BP
interaction is required for spermatogenesis (PMID:31242413).
action: KEEP_AS_NON_CORE
reason: BRCA2 is essential for meiosis, and loss causes infertility. This is a
consequence of its meiotic HR function.
- term:
id: GO:0007420
label: brain development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 loss leads to developmental defects including in brain. This is
pleiotropic.
action: MARK_AS_OVER_ANNOTATED
reason: Distal phenotypic effect of genome instability, not a specific BRCA2 function.
- term:
id: GO:0008283
label: cell population proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Generic cell proliferation term.
action: MARK_AS_OVER_ANNOTATED
reason: Too generic. BRCA2 loss affects proliferation due to genome instability,
not via direct regulation of proliferation.
- term:
id: GO:0008585
label: female gonad development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 required for meiosis which is essential for gonad development.
action: KEEP_AS_NON_CORE
reason: Downstream consequence of meiotic HR function.
- term:
id: GO:0008630
label: intrinsic apoptotic signaling pathway in response to DNA damage
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 loss leads to activation of apoptosis due to unrepaired DNA damage.
action: MARK_AS_OVER_ANNOTATED
reason: BRCA2 does not directly regulate apoptosis. Apoptosis is a downstream
consequence of HR deficiency.
- term:
id: GO:0010165
label: response to X-ray
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2-deficient cells are hypersensitive to X-rays due to defective HR
repair.
action: KEEP_AS_NON_CORE
reason: Valid but represents the phenotypic response rather than BRCA2's direct
function.
- term:
id: GO:0010225
label: response to UV-C
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Response to UV damage.
action: KEEP_AS_NON_CORE
reason: Phenotypic response to DNA damage. BRCA2 participates in repair of UV-induced
lesions via HR.
- term:
id: GO:0010332
label: response to gamma radiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 is essential for repair of gamma-radiation induced DSBs.
action: KEEP_AS_NON_CORE
reason: Phenotypic response. BRCA2 repairs radiation-induced DSBs via HR.
- term:
id: GO:0030097
label: hemopoiesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Biallelic BRCA2 mutations cause Fanconi anemia with bone marrow failure.
action: KEEP_AS_NON_CORE
reason: Downstream phenotype of BRCA2/FANCD1 deficiency. Not a direct function.
- term:
id: GO:0030330
label: DNA damage response, signal transduction by p53 class mediator
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: p53 activation occurs when BRCA2-mediated repair fails.
action: MARK_AS_OVER_ANNOTATED
reason: BRCA2 does not directly regulate p53 signaling. This is an indirect consequence.
- term:
id: GO:0031297
label: replication fork processing
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 protects stalled and reversed replication forks from nucleolytic
degradation by MRE11.
action: ACCEPT
reason: Core function. BRCA2 stabilizes RAD51 on reversed forks to prevent degradation.
This is mechanistically separable from but related to HR function.
supported_by:
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "Beyond DSB repair, BRCA2 stabilizes RAD51 on stalled/reversed\
\ replication forks to prevent nucleolytic degradation (e.g., by MRE11) and\
\ to promote restart, a function genetically and biochemically separable but\
\ coordinated with HR"
- term:
id: GO:0032465
label: regulation of cytokinesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 has been implicated in centrosome and cytokinesis regulation.
action: KEEP_AS_NON_CORE
reason: BRCA2 localizes to centrosomes and affects mitotic fidelity, but this
is secondary to HR function.
- term:
id: GO:0042771
label: intrinsic apoptotic signaling pathway in response to DNA damage by p53
class mediator
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Apoptosis induction when BRCA2-mediated repair fails.
action: MARK_AS_OVER_ANNOTATED
reason: Indirect consequence of HR deficiency, not a direct BRCA2 function.
- term:
id: GO:0043009
label: chordate embryonic development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 knockout is embryonic lethal.
action: MARK_AS_OVER_ANNOTATED
reason: Distal phenotypic effect of genome instability.
- term:
id: GO:0045931
label: positive regulation of mitotic cell cycle
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 loss causes cell cycle arrest.
action: MARK_AS_OVER_ANNOTATED
reason: BRCA2 does not directly regulate cell cycle. Cell cycle effects are consequence
of checkpoint activation.
- term:
id: GO:0051276
label: chromosome organization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 affects chromosome stability through HR repair.
action: KEEP_AS_NON_CORE
reason: Valid but vague. BRCA2 contributes to chromosome stability via its repair
function.
- term:
id: GO:0071425
label: hematopoietic stem cell proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2/FANCD1 deficiency causes bone marrow failure.
action: MARK_AS_OVER_ANNOTATED
reason: Phenotypic consequence of Fanconi anemia, not direct function.
- term:
id: GO:0072089
label: stem cell proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Generic stem cell term.
action: MARK_AS_OVER_ANNOTATED
reason: Too generic and represents phenotypic consequence.
- term:
id: GO:0090398
label: cellular senescence
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 loss can trigger senescence.
action: MARK_AS_OVER_ANNOTATED
reason: Senescence is a downstream response to DNA damage, not a BRCA2 function.
# === EXPERIMENTAL HR REPAIR EVIDENCE ===
- term:
id: GO:0000724
label: double-strand break repair via homologous recombination
evidence_type: IDA
original_reference_id: PMID:28398198
review:
summary: Functional and mutational landscapes of BRCA1 for HR and therapy resistance.
action: ACCEPT
reason: Direct experimental evidence for BRCA2's role in HR repair.
supported_by:
- reference_id: PMID:28398198
supporting_text: Functional and mutational landscapes of BRCA1 for homology-directed
repair and therapy resistance.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26833090
review:
summary: Non-catalytic roles for XPG with BRCA1 and BRCA2 in HR and genome stability.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:26833090
supporting_text: 2016 Jan 28. Non-catalytic Roles for XPG with BRCA1 and BRCA2
in Homologous Recombination and Genome Stability.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31242413
review:
summary: HSF2BP interacts with conserved domain of BRCA2 for spermatogenesis.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:31242413
supporting_text: HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required
for Mouse Spermatogenesis.
- term:
id: GO:0005515
label: protein binding
evidence_type: IDA
original_reference_id: PMID:9774970
review:
summary: Stable interaction between BRCA1 and BRCA2 in mitotic and meiotic cells.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:9774970
supporting_text: Stable interaction between the products of the BRCA1 and BRCA2
tumor suppressor genes in mitotic and meiotic cells.
- term:
id: GO:0000724
label: double-strand break repair via homologous recombination
evidence_type: IMP
original_reference_id: PMID:21719596
review:
summary: Comprehensive functional characterization of BRCA2 variants associated
with Fanconi anemia.
action: ACCEPT
reason: Mutant phenotype analysis confirms BRCA2's role in HR.
supported_by:
- reference_id: PMID:21719596
supporting_text: Jun 30. A comprehensive functional characterization of BRCA2
variants associated with Fanconi anemia using mouse ES cell-based assay.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21719596
review:
summary: BRCA2 variants characterized for functional interactions.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:21719596
supporting_text: Jun 30. A comprehensive functional characterization of BRCA2
variants associated with Fanconi anemia using mouse ES cell-based assay.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25585578
review:
summary: FBH1 influences DNA replication fork stability through RAD51 ubiquitylation.
action: REMOVE
reason: Generic protein binding is uninformative.
# === HISTONE ACETYLTRANSFERASE ACTIVITY - CONTROVERSIAL ===
supported_by:
- reference_id: PMID:25585578
supporting_text: FBH1 influences DNA replication fork stability and homologous
recombination through ubiquitylation of RAD51.
- term:
id: GO:0010484
label: histone H3 acetyltransferase activity
evidence_type: IDA
original_reference_id: PMID:9619837
review:
summary: Original 1998 paper claimed BRCA2 has intrinsic HAT activity. However,
this finding is controversial and has not been widely replicated. A 1998 study
(PMID:9824164) showed that BRCA2 associates with acetyltransferase activity
when bound to P/CAF, suggesting the HAT activity is from associated P/CAF, not
intrinsic to BRCA2.
action: UNDECIDED
reason: The claim of intrinsic HAT activity is contested. PMID:9824164 indicates
the activity comes from P/CAF association. This needs expert review.
supported_by:
- reference_id: PMID:9619837
supporting_text: The BRCA2 is a histone acetyltransferase.
- term:
id: GO:0010485
label: histone H4 acetyltransferase activity
evidence_type: IDA
original_reference_id: PMID:9619837
review:
summary: Same controversial claim as H3 HAT activity.
action: UNDECIDED
reason: Intrinsic HAT activity claim is contested. Needs expert review.
supported_by:
- reference_id: PMID:9619837
supporting_text: The BRCA2 is a histone acetyltransferase.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19423707
review:
summary: PALB2 regulates recombinational repair through chromatin association
and oligomerization.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:19423707
supporting_text: 2009 May 7. PALB2 regulates recombinational repair through
chromatin association and oligomerization.
- term:
id: GO:0000724
label: double-strand break repair via homologous recombination
evidence_type: IDA
original_reference_id: PMID:20729832
review:
summary: Purified human BRCA2 stimulates RAD51-mediated recombination. Key biochemical
study demonstrating BRCA2's direct role in HR.
action: ACCEPT
reason: High-quality direct assay evidence confirming BRCA2's role in stimulating
RAD51-dependent recombination.
supported_by:
- reference_id: PMID:20729832
supporting_text: Purified human BRCA2 stimulates RAD51-mediated recombination.
- term:
id: GO:0003697
label: single-stranded DNA binding
evidence_type: IDA
original_reference_id: PMID:20729832
review:
summary: Biochemical demonstration that purified BRCA2 binds ssDNA directly.
action: ACCEPT
reason: Direct biochemical evidence for ssDNA binding activity.
supported_by:
- reference_id: PMID:20729832
supporting_text: Purified human BRCA2 stimulates RAD51-mediated recombination.
- term:
id: GO:0002020
label: protease binding
evidence_type: IPI
original_reference_id: PMID:15314155
review:
summary: BRCA2 interacts with USP11, a deubiquitinating enzyme.
action: KEEP_AS_NON_CORE
reason: USP11 is a DUB that regulates BRCA2 stability. This is a regulatory interaction,
not core function.
supported_by:
- reference_id: PMID:15314155
supporting_text: BRCA2 is ubiquitinated in vivo and interacts with USP11, a
deubiquitinating enzyme that exhibits prosurvival function in the cellular
response to DNA damage.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12242698
review:
summary: BRCA1 and BRCA2 proteins in breast cancer.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:12242698
supporting_text: 'Highlight: BRCA1 and BRCA2 proteins in breast cancer.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15967112
review:
summary: WDRPUH interaction with BRCA2.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:15967112
supporting_text: WDRPUH, a novel WD-repeat-containing protein, is highly expressed
in human hepatocellular carcinoma and involved in cell proliferation.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11597317
review:
summary: BRCA2 and homologous recombination review.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:11597317
supporting_text: BRCA2 and homologous recombination.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15930293
review:
summary: BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:15930293
supporting_text: BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16099937
review:
summary: Analysis of albumin-associated peptides from ovarian cancer patients.
action: REMOVE
reason: Generic protein binding is uninformative. Low relevance study.
supported_by:
- reference_id: PMID:16099937
supporting_text: 2005 Aug 11. Analysis of albumin-associated peptides and proteins
from ovarian cancer patients.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16275750
review:
summary: Centrobin centriole duplication study.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:16275750
supporting_text: 'Centrobin: a novel daughter centriole-associated protein that
is required for centriole duplication.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9774970
review:
summary: BRCA1-BRCA2 interaction in mitotic and meiotic cells.
action: REMOVE
reason: Generic protein binding is uninformative.
supported_by:
- reference_id: PMID:9774970
supporting_text: Stable interaction between the products of the BRCA1 and BRCA2
tumor suppressor genes in mitotic and meiotic cells.
- term:
id: GO:0043015
label: gamma-tubulin binding
evidence_type: IPI
original_reference_id: PMID:17286961
review:
summary: BRCA2 localizes to centrosome and interacts with gamma-tubulin. Interference
leads to abnormal nuclear division.
action: KEEP_AS_NON_CORE
reason: BRCA2 does localize to centrosomes and binds gamma-tubulin, but this is
secondary to its HR function.
supported_by:
- reference_id: PMID:17286961
supporting_text: Interference with BRCA2, which localizes to the centrosome
during S and early M phase, leads to abnormal nuclear division.
- term:
id: GO:0004402
label: histone acetyltransferase activity
evidence_type: IDA
original_reference_id: PMID:9824164
negated: true
review:
summary: BRCA2 associates with acetyltransferase activity when bound to P/CAF.
This study shows HAT activity comes from P/CAF, not BRCA2 itself.
action: REMOVE
reason: This annotation has a NOT qualifier in the GOA file, meaning BRCA2 does
NOT have intrinsic HAT activity. The activity comes from associated P/CAF.
# === CELLULAR COMPONENT - NUCLEUS ===
supported_by:
- reference_id: PMID:9824164
supporting_text: BRCA2 associates with acetyltransferase activity when bound
to P/CAF.
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: BRCA2 is predominantly nuclear where it functions in DNA repair.
action: ACCEPT
reason: Core localization. BRCA2 must be nuclear to perform its DNA repair function.
- term:
id: GO:0006355
label: regulation of DNA-templated transcription
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: BRCA2 has been reported to have transcriptional activation activity in
its N-terminal domain.
action: KEEP_AS_NON_CORE
reason: BRCA2 contains a transcriptional activation domain and has been shown
to activate transcription (PMID:9126734), but this is not its primary function.
- term:
id: GO:0006338
label: chromatin remodeling
evidence_type: IEA
original_reference_id: GO_REF:0000108
review:
summary: Inferred from claimed HAT activity.
action: UNDECIDED
reason: This inference depends on the contested HAT activity claim. Needs expert
review.
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Nuclear localization.
action: ACCEPT
reason: Consistent with known nuclear function.
- term:
id: GO:0005813
label: centrosome
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: BRCA2 localizes to centrosomes during S and early M phase.
action: KEEP_AS_NON_CORE
reason: BRCA2 does localize to centrosomes (PMID:17286961, PMID:21276791) but
this is secondary to its nuclear DNA repair function.
- term:
id: GO:0006310
label: DNA recombination
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Parent term of HR.
action: ACCEPT
reason: Valid. BRCA2 is a key recombination mediator.
- term:
id: GO:0006974
label: DNA damage response
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: BRCA2 is part of the DNA damage response.
action: ACCEPT
reason: BRCA2 is recruited to and functions at DNA damage sites.
- term:
id: GO:0000152
label: nuclear ubiquitin ligase complex
evidence_type: IDA
original_reference_id: PMID:14636569
review:
summary: BRCA2 is part of the BRCC holoenzyme complex which contains BRCA1 and
has ubiquitin ligase activity.
action: ACCEPT
reason: BRCA2 is part of multi-protein DNA repair complexes with ubiquitin ligase
activity.
supported_by:
- reference_id: PMID:14636569
supporting_text: Regulation of BRCC, a holoenzyme complex containing BRCA1 and
BRCA2, by a signalosome-like subunit and its role in DNA repair.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:14636569
review:
summary: Nuclear localization is essential for BRCA2's role in homologous recombination
DNA repair.
action: ACCEPT
reason: Nuclear localization is core to BRCA2 function in DNA repair, directly
demonstrated by IDA evidence.
supported_by:
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "BRCA2 is predominantly nuclear and accumulates at DNA double-strand\
\ breaks, ssDNA gaps, and stressed/reversed replication forks"
- reference_id: PMID:14636569
supporting_text: Regulation of BRCC, a holoenzyme complex containing BRCA1 and
BRCA2, by a signalosome-like subunit and its role in DNA repair.
- term:
id: GO:0071479
label: cellular response to ionizing radiation
evidence_type: IMP
original_reference_id: PMID:14636569
review:
summary: BRCA2 is required for proper response to ionizing radiation.
action: ACCEPT
reason: BRCA2 is essential for repair of radiation-induced DSBs via HR.
supported_by:
- reference_id: PMID:14636569
supporting_text: Regulation of BRCC, a holoenzyme complex containing BRCA1 and
BRCA2, by a signalosome-like subunit and its role in DNA repair.
- term:
id: GO:2000001
label: regulation of DNA damage checkpoint
evidence_type: NAS
original_reference_id: PMID:14636569
review:
summary: BRCA2 participates in checkpoint regulation.
action: KEEP_AS_NON_CORE
reason: BRCA2 affects checkpoint signaling but is not a direct checkpoint regulator.
# === ADDITIONAL CELLULAR COMPONENT ANNOTATIONS ===
supported_by:
- reference_id: PMID:14636569
supporting_text: Regulation of BRCC, a holoenzyme complex containing BRCA1 and
BRCA2, by a signalosome-like subunit and its role in DNA repair.
- term:
id: GO:0005694
label: chromosome
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 associates with chromosomes at DNA damage sites.
action: ACCEPT
reason: BRCA2 is recruited to chromosomal DNA damage sites.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Some BRCA2 is cytoplasmic before nuclear import.
action: KEEP_AS_NON_CORE
reason: BRCA2 is predominantly nuclear but some cytoplasmic localization exists.
- term:
id: GO:0007141
label: male meiosis I
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 is required for meiotic recombination.
action: KEEP_AS_NON_CORE
reason: BRCA2 functions in meiotic HR, essential for meiosis I.
- term:
id: GO:0070200
label: establishment of protein localization to telomere
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: BRCA2 facilitates RAD51 localization to telomeres.
action: KEEP_AS_NON_CORE
reason: BRCA2 loads RAD51 at telomeres for replication (PMID:21076401).
- term:
id: GO:0005634
label: nucleus
evidence_type: NAS
original_reference_id: PMID:19369211
review:
summary: Nuclear localization in BRCA complex.
action: ACCEPT
reason: Consistent with established nuclear function.
supported_by:
- reference_id: PMID:19369211
supporting_text: PALB2 is an integral component of the BRCA complex required
for homologous recombination repair.
- term:
id: GO:1990391
label: DNA repair complex
evidence_type: IPI
original_reference_id: PMID:19369211
review:
summary: BRCA2 is part of the BRCA complex with BRCA1 and PALB2 required for HR
repair.
action: ACCEPT
reason: Core component of DNA repair complex.
supported_by:
- reference_id: PMID:19369211
supporting_text: PALB2 is an integral component of the BRCA complex required
for homologous recombination repair.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: BRCA2 localizes to the nucleoplasm where it participates in DNA repair
processes.
action: ACCEPT
reason: Nucleoplasm localization is consistent with BRCA2's role in nuclear DNA
repair machinery.
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: Some BRCA2 is present in cytosol.
action: KEEP_AS_NON_CORE
reason: BRCA2 is predominantly nuclear; cytosolic localization is secondary.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9763200
review:
summary: Reactome pathway annotation for cytosolic BRCA2.
action: KEEP_AS_NON_CORE
reason: Secondary localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9709571
review:
summary: Reactome pathway annotation.
action: ACCEPT
reason: Consistent with nuclear function.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:26833090
review:
summary: Nuclear localization with XPG in HR complex.
action: ACCEPT
reason: Consistent with nuclear DNA repair function.
supported_by:
- reference_id: PMID:26833090
supporting_text: 2016 Jan 28. Non-catalytic Roles for XPG with BRCA1 and BRCA2
in Homologous Recombination and Genome Stability.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:26833090
review:
summary: BRCA2 is part of HR protein complex.
action: ACCEPT
reason: BRCA2 functions in multi-protein complexes.
supported_by:
- reference_id: PMID:26833090
supporting_text: 2016 Jan 28. Non-catalytic Roles for XPG with BRCA1 and BRCA2
in Homologous Recombination and Genome Stability.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9709601
review:
summary: Reactome pathway annotation.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9709268
review:
summary: Reactome pathway annotation.
action: KEEP_AS_NON_CORE
reason: Secondary localization.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9709273
review:
summary: Reactome pathway annotation.
action: KEEP_AS_NON_CORE
reason: Secondary localization.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9763137
review:
summary: Reactome pathway - BRCA2 binds SEM1(DSS1).
action: KEEP_AS_NON_CORE
reason: Secondary localization.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:9774970
review:
summary: BRCA1-BRCA2 complex in mitotic and meiotic cells.
action: ACCEPT
reason: BRCA2 forms complexes with BRCA1 and other HR proteins.
supported_by:
- reference_id: PMID:9774970
supporting_text: Stable interaction between the products of the BRCA1 and BRCA2
tumor suppressor genes in mitotic and meiotic cells.
- term:
id: GO:0000800
label: lateral element
evidence_type: IDA
original_reference_id: PMID:9774970
review:
summary: BRCA2 localizes to synaptonemal complex lateral elements during meiosis.
action: KEEP_AS_NON_CORE
reason: Meiosis-specific localization for meiotic HR function.
supported_by:
- reference_id: PMID:9774970
supporting_text: Stable interaction between the products of the BRCA1 and BRCA2
tumor suppressor genes in mitotic and meiotic cells.
- term:
id: GO:0000781
label: chromosome, telomeric region
evidence_type: IDA
original_reference_id: PMID:21076401
review:
summary: BRCA2 acts as RAD51 loader at telomeres for telomere replication and
capping.
action: KEEP_AS_NON_CORE
reason: Telomeric localization for HR-dependent telomere maintenance.
supported_by:
- reference_id: PMID:21076401
supporting_text: Nov 14. BRCA2 acts as a RAD51 loader to facilitate telomere
replication and capping.
- term:
id: GO:0070200
label: establishment of protein localization to telomere
evidence_type: IDA
original_reference_id: PMID:21076401
review:
summary: BRCA2 localizes RAD51 to telomeres.
action: KEEP_AS_NON_CORE
reason: Extension of BRCA2's RAD51 loading function to telomeres.
supported_by:
- reference_id: PMID:21076401
supporting_text: Nov 14. BRCA2 acts as a RAD51 loader to facilitate telomere
replication and capping.
- term:
id: GO:1990426
label: mitotic recombination-dependent replication fork processing
evidence_type: IMP
original_reference_id: PMID:21076401
review:
summary: BRCA2 required for recombination-dependent fork processing at telomeres.
action: ACCEPT
reason: Core function - BRCA2's role in replication fork processing is well-established.
# === ADDITIONAL NUCLEOPLASM TAS ANNOTATIONS FROM REACTOME ===
supported_by:
- reference_id: PMID:21076401
supporting_text: Nov 14. BRCA2 acts as a RAD51 loader to facilitate telomere
replication and capping.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5685242
review:
summary: Reactome - CHEK1 phosphorylates BRCA2.
action: ACCEPT
reason: Nucleoplasm localization during checkpoint signaling.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5685341
review:
summary: Reactome - BCDX2 complex stabilizes RAD51 filament.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5685838
review:
summary: Reactome - CX3 complex binds D-loop.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5686410
review:
summary: Reactome - BLM mediates dissolution of double Holliday junction.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5686440
review:
summary: Reactome - MUS81:EME1,EME2 cleaves D-loop.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5686469
review:
summary: Reactome - Resolution of D-loops.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5686483
review:
summary: Reactome - Resolution of Holliday junctions.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5693539
review:
summary: Reactome - Ligation of DNA and Holliday structure formation.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5693561
review:
summary: Reactome - RAD51 binds BRCA2 at resected DSBs.
action: ACCEPT
reason: Core nucleoplasm localization for HR.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5693584
review:
summary: Reactome - Cleavage of Holliday junctions.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5693589
review:
summary: Reactome - D-loop dissociation and strand annealing.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5693593
review:
summary: Reactome - D-loop extension by DNA polymerases.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5693620
review:
summary: Reactome - D-loop formation mediated by PALB2, BRCA2 and RAD51.
action: ACCEPT
reason: Core nucleoplasm localization for HR function.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9701199
review:
summary: Reactome - Defective D-loop formation due to BRCA1 loss.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9704330
review:
summary: Reactome - Defective D-loop formation due to PALB2 loss.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9704408
review:
summary: Reactome - Defective D-loop formation.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9853389
review:
summary: Reactome - FIGNL1 binds RAD51.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0005813
label: centrosome
evidence_type: IDA
original_reference_id: PMID:21276791
review:
summary: HR proteins including BRCA2 associate with centrosomes.
action: KEEP_AS_NON_CORE
reason: Centrosome localization is secondary to nuclear DNA repair function.
supported_by:
- reference_id: PMID:21276791
supporting_text: Epub 2011 Jan 27. Homologous recombination proteins are associated
with centrosomes and are required for mitotic stability.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9709273
review:
summary: Reactome - BRCA2 translocates to nucleus.
action: ACCEPT
reason: Nucleoplasm localization.
- term:
id: GO:0051298
label: centrosome duplication
evidence_type: IMP
original_reference_id: PMID:17286961
review:
summary: BRCA2 interference leads to abnormal centrosome duplication.
action: KEEP_AS_NON_CORE
reason: BRCA2 affects centrosome function but this is secondary to HR.
supported_by:
- reference_id: PMID:17286961
supporting_text: Interference with BRCA2, which localizes to the centrosome
during S and early M phase, leads to abnormal nuclear division.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:9126734
review:
summary: BRCA2 contains transcriptional activation functions in its N-terminus.
action: KEEP_AS_NON_CORE
reason: BRCA2 has transcriptional activation activity but this is not its primary
function.
supported_by:
- reference_id: PMID:9126734
supporting_text: Transcriptional activation functions in BRCA2.
- term:
id: GO:0033593
label: BRCA2-MAGE-D1 complex
evidence_type: IDA
original_reference_id: PMID:15930293
review:
summary: BRCA2 forms complex with MAGE-D1 to suppress cell proliferation.
action: KEEP_AS_NON_CORE
reason: This complex has anti-proliferative function but is not central to BRCA2's
HR role.
supported_by:
- reference_id: PMID:15930293
supporting_text: BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
- term:
id: GO:0033600
label: negative regulation of mammary gland epithelial cell proliferation
evidence_type: IDA
original_reference_id: PMID:15930293
review:
summary: BRCA2-MAGE-D1 complex suppresses mammary epithelial proliferation.
action: KEEP_AS_NON_CORE
reason: Anti-proliferative function is tissue-specific and secondary.
supported_by:
- reference_id: PMID:15930293
supporting_text: BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:17286961
review:
summary: Nuclear localization during S and early M phase.
action: ACCEPT
reason: Core nuclear localization.
supported_by:
- reference_id: PMID:17286961
supporting_text: Interference with BRCA2, which localizes to the centrosome
during S and early M phase, leads to abnormal nuclear division.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:9560268
review:
summary: Nuclear localization for RAD51 binding.
action: ACCEPT
reason: Core nuclear localization.
supported_by:
- reference_id: PMID:9560268
supporting_text: The BRC repeats in BRCA2 are critical for RAD51 binding and
resistance to methyl methanesulfonate treatment.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:9774970
review:
summary: Nuclear localization in mitotic and meiotic cells.
action: ACCEPT
reason: Core nuclear localization.
supported_by:
- reference_id: PMID:9774970
supporting_text: Stable interaction between the products of the BRCA1 and BRCA2
tumor suppressor genes in mitotic and meiotic cells.
- term:
id: GO:0005813
label: centrosome
evidence_type: IDA
original_reference_id: PMID:17286961
review:
summary: Centrosome localization during S and early M phase.
action: KEEP_AS_NON_CORE
reason: Secondary localization.
supported_by:
- reference_id: PMID:17286961
supporting_text: Interference with BRCA2, which localizes to the centrosome
during S and early M phase, leads to abnormal nuclear division.
- term:
id: GO:0006289
label: nucleotide-excision repair
evidence_type: IMP
original_reference_id: PMID:16845393
review:
summary: BRCA2 role in replication-coupled DNA interstrand cross-link repair.
action: KEEP_AS_NON_CORE
reason: BRCA2's primary role is HR, but it participates in ICL repair which involves
NER components.
supported_by:
- reference_id: PMID:16845393
supporting_text: Jul 16. The role of BRCA2 in replication-coupled DNA interstrand
cross-link repair in vitro.
- term:
id: GO:0006302
label: double-strand break repair
evidence_type: IMP
original_reference_id: PMID:16845393
review:
summary: BRCA2 required for DSB repair in ICL repair context.
action: ACCEPT
reason: DSB repair is a core BRCA2 function.
supported_by:
- reference_id: PMID:16845393
supporting_text: Jul 16. The role of BRCA2 in replication-coupled DNA interstrand
cross-link repair in vitro.
- term:
id: GO:0030141
label: secretory granule
evidence_type: IDA
original_reference_id: PMID:8589722
review:
summary: Old study claiming BRCA1 secretion and granin properties. Reference seems
to be about BRCA1 not BRCA2.
action: UNDECIDED
reason: This reference (PMID:8589722) appears to be about BRCA1, not BRCA2. Possible
annotation error. Needs verification.
# === NEW ANNOTATIONS (suggested additions) ===
supported_by:
- reference_id: PMID:8589722
supporting_text: BRCA1 is secreted and exhibits properties of a granin.
- term:
id: GO:0000730
label: DNA recombinase assembly
evidence_type: IEA
review:
summary: BRCA2 facilitates RAD51 recombinase assembly on single-stranded DNA by
targeting RAD51 to ssDNA over dsDNA, enabling RAD51 to displace RPA and stabilizing
RAD51-ssDNA nucleoprotein filaments.
action: NEW
reason: BRCA2 promotes assembly of RAD51 onto single-stranded DNA. This is a core
function essential for homologous recombination repair. Well-supported by biochemical
studies.
supported_by:
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "BRCA2 mediates homologous recombination (HR) by loading and\
\ stabilizing the recombinase RAD51 on resected single-stranded DNA (ssDNA)\
\ to form the presynaptic filament required for homology search and strand\
\ exchange"
- term:
id: GO:0042148
label: DNA strand invasion
evidence_type: IEA
review:
summary: BRCA2 facilitates strand invasion during homologous recombination by
promoting RAD51 nucleoprotein filament formation. BRCA2 may also play a role
in the extension step after strand invasion at replication-dependent DSBs.
action: NEW
reason: BRCA2 promotes RAD51 filament formation which is essential for strand
invasion during HR. Working with PALB2, BRCA2 is involved in POLH localization
at collapsed forks and DNA polymerization.
supported_by:
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "D-loop formation mediated by PALB2, BRCA2 and RAD51"
references:
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara.
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods.
findings: []
- id: PMID:10373512
title: Interaction between the product of the breast cancer susceptibility gene
BRCA2 and DSS1, a protein functionally conserved from yeast to mammals.
findings: []
- id: PMID:10551859
title: Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51
complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint
control.
findings: []
- id: PMID:11597317
title: BRCA2 and homologous recombination.
findings: []
- id: PMID:12242698
title: 'Highlight: BRCA1 and BRCA2 proteins in breast cancer.'
findings: []
- id: PMID:12442171
title: Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.
findings: []
- id: PMID:15115758
title: Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.
findings: []
- id: PMID:15314155
title: BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating
enzyme that exhibits prosurvival function in the cellular response to DNA damage.
findings: []
- id: PMID:15800615
title: CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational
repair.
findings: []
- id: PMID:15930293
title: BRCA2 suppresses cell proliferation via stabilizing MAGE-D1.
findings: []
- id: PMID:15967112
title: WDRPUH, a novel WD-repeat-containing protein, is highly expressed in human
hepatocellular carcinoma and involved in cell proliferation.
findings: []
- id: PMID:16099937
title: Analysis of albumin-associated peptides and proteins from ovarian cancer
patients.
findings: []
- id: PMID:16205630
title: DSS1 is required for the stability of BRCA2.
findings: []
- id: PMID:16275750
title: 'Centrobin: a novel daughter centriole-associated protein that is required
for centriole duplication.'
findings: []
- id: PMID:17286961
title: Interference with BRCA2, which localizes to the centrosome during S and early
M phase, leads to abnormal nuclear division.
findings: []
- id: PMID:17420451
title: Analysis of PALB2/FANCN-associated breast cancer families.
findings: []
- id: PMID:17515903
title: Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly
by BRC repeats.
findings: []
- id: PMID:17515904
title: Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of
BRCA2.
findings: []
- id: PMID:17541404
title: Interactions between human BRCA2 protein and the meiosis-specific recombinase
DMC1.
findings: []
- id: PMID:18212739
title: FANCG promotes formation of a newly identified protein complex containing
BRCA2, FANCD2 and XRCC3.
findings: []
- id: PMID:18264088
title: Resistance to therapy caused by intragenic deletion in BRCA2.
findings: []
- id: PMID:19303847
title: The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51.
findings: []
- id: PMID:19369211
title: PALB2 is an integral component of the BRCA complex required for homologous
recombination repair.
findings: []
- id: PMID:19423707
title: PALB2 regulates recombinational repair through chromatin association and
oligomerization.
findings: []
- id: PMID:19609323
title: Structural basis for recruitment of BRCA2 by PALB2.
findings: []
- id: PMID:19628690
title: The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single-
versus double-stranded DNA to stimulate strand exchange.
findings: []
- id: PMID:20421506
title: Mapping the physical and functional interactions between the tumor suppressors
p53 and BRCA2.
findings: []
- id: PMID:20729832
title: Purified human BRCA2 stimulates RAD51-mediated recombination.
findings: []
- id: PMID:20729859
title: Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded
DNA.
findings: []
- id: PMID:21076401
title: BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping.
findings: []
- id: PMID:21276791
title: Homologous recombination proteins are associated with centrosomes and are
required for mitotic stability.
findings: []
- id: PMID:21399666
title: A mitotic function for the high-mobility group protein HMG20b regulated by
its interaction with the BRC repeats of the BRCA2 tumor suppressor.
findings: []
- id: PMID:21601571
title: Valine 1532 of human BRC repeat 4 plays an important role in the interaction
between BRCA2 and RAD51.
findings: []
- id: PMID:21719596
title: A comprehensive functional characterization of BRCA2 variants associated
with Fanconi anemia using mouse ES cell-based assay.
findings: []
- id: PMID:22116401
title: Synaptonemal complex protein SYCP3 impairs mitotic recombination by interfering
with BRCA2.
findings: []
- id: PMID:22193777
title: ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates
DNA repair.
findings: []
- id: PMID:22293751
title: APRIN is a cell cycle specific BRCA2-interacting protein required for genome
integrity and a predictor of outcome after chemotherapy in breast cancer.
findings: []
- id: PMID:24013206
title: A cancer-associated BRCA2 mutation reveals masked nuclear export signals
controlling localization.
findings: []
- id: PMID:24141787
title: Breast cancer-associated missense mutants of the PALB2 WD40 domain, which
directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
findings: []
- id: PMID:24485656
title: 'Breast cancer proteins PALB2 and BRCA2 stimulate polymerase η in recombination-associated
DNA synthesis at blocked replication forks.'
findings: []
- id: PMID:24981860
title: Human-chromatin-related protein interactions identify a demethylase complex
required for chromosome segregation.
findings: []
- id: PMID:25282148
title: Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor.
findings: []
- id: PMID:25585578
title: FBH1 influences DNA replication fork stability and homologous recombination
through ubiquitylation of RAD51.
findings: []
- id: PMID:26833090
title: Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination
and Genome Stability.
findings: []
- id: PMID:28319063
title: Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.
findings: []
- id: PMID:28398198
title: Functional and mutational landscapes of BRCA1 for homology-directed repair
and therapy resistance.
findings: []
- id: PMID:30410870
title: Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2
Protein Interaction.
findings: []
- id: PMID:31242413
title: HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse
Spermatogenesis.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
findings: []
- id: PMID:34591612
title: A protein interaction landscape of breast cancer.
findings: []
- id: PMID:39009827
title: Proteome-scale characterisation of motif-based interactome rewiring by disease
mutations.
findings: []
- id: PMID:9560268
title: The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to
methyl methanesulfonate treatment.
findings: []
- id: PMID:9619837
title: The BRCA2 is a histone acetyltransferase.
findings: []
- id: PMID:9774970
title: Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor
genes in mitotic and meiotic cells.
findings: []
- id: PMID:9824164
title: BRCA2 associates with acetyltransferase activity when bound to P/CAF.
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt.
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
links.
findings: []
- id: PMID:14636569
title: Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a
signalosome-like subunit and its role in DNA repair.
findings: []
- id: PMID:16845393
title: The role of BRCA2 in replication-coupled DNA interstrand cross-link repair
in vitro.
findings: []
- id: PMID:8589722
title: BRCA1 is secreted and exhibits properties of a granin.
findings: []
- id: PMID:9126734
title: Transcriptional activation functions in BRCA2.
findings: []
- id: Reactome:R-HSA-5685242
title: CHEK1 phosphorylates BRCA2
findings: []
- id: Reactome:R-HSA-5685341
title: BCDX2 complex stabilizes RAD51 filament
findings: []
- id: Reactome:R-HSA-5685838
title: CX3 complex binds D-loop structures
findings: []
- id: Reactome:R-HSA-5686410
title: BLM mediates dissolution of double Holliday junction
findings: []
- id: Reactome:R-HSA-5686440
title: MUS81:EME1,EME2 cleaves D-loop
findings: []
- id: Reactome:R-HSA-5686469
title: Resolution of D-loops cleaved by MUS81:EME1 or MUS81:EME2
findings: []
- id: Reactome:R-HSA-5686483
title: Resolution of Holliday junctions cleaved by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)
findings: []
- id: Reactome:R-HSA-5693539
title: Ligation of DNA and formation of Holliday structures following repair synthesis
findings: []
- id: Reactome:R-HSA-5693561
title: RAD51 binds BRCA2 at resected DNA DSBs
findings: []
- id: Reactome:R-HSA-5693584
title: Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)
findings: []
- id: Reactome:R-HSA-5693589
title: D-loop dissociation and strand annealing
findings: []
- id: Reactome:R-HSA-5693593
title: D-loop extension by DNA polymerases
findings: []
- id: Reactome:R-HSA-5693620
title: D-loop formation mediated by PALB2, BRCA2 and RAD51
findings: []
- id: Reactome:R-HSA-9701199
title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
of BRCA1 in PALB2 binding
findings: []
- id: Reactome:R-HSA-9704330
title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
of PALB2 in BRCA1 binding
findings: []
- id: Reactome:R-HSA-9704408
title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
of PALB2 in binding to BRCA2/RAD51/RAD51C
findings: []
- id: Reactome:R-HSA-9709268
title: Defective BRCA2 does not translocate to the nucleus
findings: []
- id: Reactome:R-HSA-9709273
title: BRCA2 translocates to the nucleus
findings: []
- id: Reactome:R-HSA-9709571
title: BRCA2 mutants with BRC defects or a defect in the C-terminal RAD51 binding
site do not bind RAD51
findings: []
- id: Reactome:R-HSA-9709601
title: Defective recruitment of BRCA2 and RAD51 due to loss of BRCA2 function in
PALB2 binding
findings: []
- id: Reactome:R-HSA-9763137
title: BRCA2 binds SEM1 (DSS1)
findings: []
- id: Reactome:R-HSA-9763200
title: BRCA2 mutants do not bind SEM1 (DSS1)
findings: []
- id: Reactome:R-HSA-9853389
title: FIGNL1 binds RAD51
findings: []
- id: file:human/BRCA2/BRCA2-deep-research-falcon.md
title: Deep research on BRCA2 function
findings: []
core_functions:
- description: Loads and stabilizes RAD51 recombinase onto RPA-coated single-stranded
DNA to form the presynaptic filament required for homology search and strand exchange
during homologous recombination DNA repair
molecular_function:
id: GO:0003697
label: single-stranded DNA binding
directly_involved_in:
- id: GO:0000724
label: double-strand break repair via homologous recombination
- id: GO:0000730
label: DNA recombinase assembly
- id: GO:0042148
label: DNA strand invasion
locations:
- id: GO:0005634
label: nucleus
- id: GO:0005654
label: nucleoplasm
in_complex:
id: GO:1990391
label: DNA repair complex
supported_by:
- reference_id: PMID:20729832
supporting_text: "Purified human BRCA2 stimulates RAD51-mediated recombination"
- reference_id: PMID:19369211
supporting_text: "PALB2 is an integral component of the BRCA complex required\
\ for homologous recombination repair"
- reference_id: PMID:9560268
supporting_text: "The BRC repeats in BRCA2 are critical for RAD51 binding and\
\ resistance to methyl methanesulfonate treatment"
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "BRCA2 is a genome maintenance factor that mediates homologous\
\ recombination (HR) by loading and stabilizing the recombinase RAD51 on resected\
\ single-stranded DNA (ssDNA) to form the presynaptic filament required for\
\ homology search and strand exchange"
- description: Protects stalled and reversed replication forks from MRE11-mediated
nucleolytic degradation by stabilizing RAD51 on nascent DNA
molecular_function:
id: GO:0003697
label: single-stranded DNA binding
directly_involved_in:
- id: GO:0031297
label: replication fork processing
- id: GO:1990426
label: mitotic recombination-dependent replication fork processing
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: file:human/BRCA2/BRCA2-deep-research-falcon.md
supporting_text: "Beyond DSB repair, BRCA2 stabilizes RAD51 on stalled/reversed\
\ replication forks to prevent nucleolytic degradation (e.g., by MRE11) and\
\ to promote restart, a function genetically and biochemically separable but\
\ coordinated with HR"
status: COMPLETE