RAD51C (RAD51 paralog C; RAD51L2; DNA repair protein RAD51 homolog 3; FANCO) is one of five human RAD51 paralogs and the only one shared between the two paralog complexes: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). It is a RecA/RAD51-family protein with Walker A/B nucleotide-binding motifs that binds single-stranded DNA and branched DNA structures such as replication forks and Holliday junctions. Within its complexes it acts as a mediator of homologous recombination: through coupled ATP binding and hydrolysis it promotes nucleation and extension of the RAD51 recombinase nucleoprotein filament on RPA-coated single-stranded DNA. BCDX2 acts early, downstream of BRCA2 and upstream of RAD51 loading, to assemble and stabilize RAD51 filaments and to protect and restart stalled replication forks; CX3 acts later, binding D-loop and Holliday-junction intermediates and promoting branch migration and resolution. RAD51C is required for repair of DNA double-strand breaks and interstrand crosslinks, for RAD51 focus formation, sister chromatid cohesion, and genome stability. It also accumulates at damage sites (dependent on ATM, NBS1 and RPA) and facilitates activation of the CHK2 checkpoint kinase, coupling damage sensing to cell-cycle arrest. Additional reported roles include maintenance of mitochondrial DNA copy number under oxidative stress and meiotic recombination. Biallelic loss of function causes a Fanconi anemia-like disorder (complementation group O, FANCO); monoallelic germline mutations predispose to hereditary breast and ovarian cancer (BROVCA3).
Definition: Binding to a DNA strand exchange protein (recombinase) and to single-stranded DNA so as to promote nucleation and extension of the recombinase nucleoprotein filament, including displacement of the single-stranded DNA-binding protein that otherwise occludes the substrate. The loader is not itself a strand exchange protein and does not catalyse strand exchange.
Justification: GO has the process term GO:0000730 DNA recombinase assembly but no molecular function for the activity that carries it out. That gap is why RAD51C's mediator role has been annotated with borrowed terms: an InterPro-derived IEA supplies GO:0140664 ATP-dependent DNA damage sensor activity, which describes a sensor rather than a loader and which the sibling XRCC2 review in this same cohort marks as a RecA/RAD51-family over-propagation, while the alternative GO:0097435 supramolecular fiber organization is a generic parent that loses the recombinase identity entirely. The RAD51 paralog complexes BCDX2 and CX3 are the clearest use case - BCDX2 "stimulates the nucleation and extension of RAD51" on RPA-coated ssDNA in an ATP-hydrolysis-dependent manner - and the same term would serve BRCA2, RAD52 and the bacterial RecFOR and RecBCD loaders, none of which has a molecular function for this activity either.
Parent term: single-stranded DNA binding
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005657 replication fork | IBA GO_REF:0000033 | ACCEPT | Summary: RAD51C-containing paralog complexes (BCDX2 and CX3) localize to and act at replication forks. Well supported by direct EM visualization of both complexes bound to forked DNA. Reason: Consistent with experimental evidence that BCDX2 and CX3 bind replication-fork DNA and function in fork protection/restart. The IBA localization is at an appropriate level. Supporting Evidence: PMID:20207730 binding of BCDX2 and CX3 to DNA templates containing replication forks and |
| GO:0008821 crossover junction DNA endonuclease activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: RAD51C participates in Holliday-junction branch migration and resolution as part of CX3, but it is a RecA-fold ATPase mediator with no nuclease catalytic residues; the endonucleolytic cleavage activity itself is not a molecular function of RAD51C. Reason: Depletion of RAD51C reduces branch migration and HJ resolvase activity in extracts (PMID:14716019), but the actual endonuclease/resolvase catalysis was subsequently attributed to GEN1 acting with XRCC3; RAD51C contributes to processing without itself catalyzing junction cleavage. Assigning the endonuclease molecular function to RAD51C (even with contributes_to) over-annotates its biochemistry. Its role in HJ processing is better captured by DNA recombination / DSB-repair-via-HR terms. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION PSEUDO OR SUBACTIVITY LOSS Supporting Evidence: PMID:23108668 XRCC3 functions jointly with GEN1 later PMID:23108668 at the stage of Holliday junction resolution |
| GO:0033065 Rad51C-XRCC3 complex | IBA GO_REF:0000033 | ACCEPT | Summary: RAD51C is a subunit of the CX3 complex (RAD51C-XRCC3). Directly demonstrated by complex purification. Reason: Core, well-established complex membership supported by biochemical purification. Supporting Evidence: PMID:11751635 the five paralogs exist in two distinct complexes in human cells |
| GO:0000400 four-way junction DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: RAD51C-containing complexes bind Holliday junctions (four-way junctions) with high specificity, as visualized by EM. Reason: Direct experimental support; contributes_to is appropriate since binding is a property of the assembled paralog complex. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally high specificity to the DNA junctions |
| GO:0000707 meiotic DNA recombinase assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: RAD51 paralogs promote recombinase (RAD51/DMC1) filament assembly, including in meiosis; inferred phylogenetically from yeast Rad55/Rad57-type mediators and supported by the mammalian mediator role in RAD51 filament assembly. Reason: Meiotic recombinase assembly is a plausible conserved role, but for human RAD51C the dominant, experimentally characterized function is mitotic/somatic HR mediation. Retained as a non-core, meiosis-specific function. Supported in the mouse ortholog: hypomorphic Rad51c spermatocytes arrest in early meiotic prophase I, evidencing a role in early RAD51-mediated (recombinase-assembly) meiotic recombination. Supporting Evidence: PMID:17312021 providing evidence for the role of RAD51C in early stages of RAD51-mediated recombination |
| GO:0007131 reciprocal meiotic recombination | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred meiotic crossover recombination role, consistent with the RAD51 paralog family's function in recombination. Reason: Legitimate conserved meiotic role but not the core somatic HR-mediator function that defines human RAD51C. Kept as non-core. Corroborated by mouse data: RAD51C localizes to meiotic chromosomes and the RAD51C-XRCC3 resolvase complex associates with crossovers, resolving recombination intermediates before chromosome segregation. Supporting Evidence: PMID:17114795 associates with crossovers and may play an essential role in the resolution of recombination intermediates prior to chromosome segregation |
| GO:0033063 Rad51B-Rad51C-Rad51D-XRCC2 complex | IBA GO_REF:0000033 | ACCEPT | Summary: RAD51C is a subunit of the BCDX2 complex (RAD51B-RAD51C-RAD51D-XRCC2). Reason: Core complex membership, directly demonstrated by purification and cryo-EM. Supporting Evidence: PMID:11751635 the five paralogs exist in two distinct complexes in human cells |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: RAD51C (within BCDX2/CX3) binds single-stranded, branched and duplex DNA. The generic DNA-binding term is accurate though broad. Reason: Supported by biochemical DNA-binding data for the complexes; a valid parent term. More specific activities (ssDNA binding, four-way junction binding) are captured separately. Supporting Evidence: PMID:11751635 BCDX2 binds single-stranded DNA and single-stranded gaps in duplex DNA |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: RAD51C has a Walker A/B P-loop (residues 125-132) and binds ATP; ATP binding/hydrolysis is essential for its mediator function. Reason: Supported by conserved Walker motifs and by functional requirement of the ATP-binding domain (K131 mutagenesis) for RAD51C activity. Supporting Evidence: PMID:12966089 reduced homology-directed repair of a DNA double-strand break by gene |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: RAD51C is a nuclear protein acting in nuclear HR; also has cytoplasmic pools. Reason: Consistent with GFP-tagging and immunofluorescence localizing RAD51C to the nucleus. Supporting Evidence: PMID:12966089 the protein is localized |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: A cytoplasmic/perinuclear pool of RAD51C exists and regulates RAD51 stability; damage induces nuclear redistribution. Reason: Supported by detection of endogenous cytoplasmic Rad51C. Supporting Evidence: PMID:16215984 detect endogenous Rad51C |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: RAD51C is present in human mitochondria, where it (with RAD51 and XRCC3) maintains mtDNA copy number under oxidative stress. Reason: Directly demonstrated mitochondrial localization; a genuine non-core localization. Supporting Evidence: PMID:20413593 Rad51 and the related HR proteins Rad51C and Xrcc3 exist in human mitochondria |
| GO:0006281 DNA repair | IEA GO_REF:0000002 | ACCEPT | Summary: RAD51C is essential for DNA repair, principally via homologous recombination. Reason: Broad but accurate parent; captured more specifically by DSB-repair-via-HR. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A perinuclear cytoplasmic pool of RAD51C is observed; this is a peripheral localization relative to its core nuclear HR function. Reason: Supported by localization studies but not part of the core HR-mediator activity. Supporting Evidence: PMID:16215984 detect endogenous Rad51C |
| GO:0003697 single-stranded DNA binding | IDA PMID:11751636 Mediator function of the human Rad51B-Rad51C complex in Rad5... | NEW | Summary: Proposed new annotation. The Rad51B-Rad51C complex has directly demonstrated ssDNA binding and ssDNA-stimulated ATPase activity, which is the substrate-engagement half of the recombination-mediator role. contributes_to, because the activity is measured on the complex rather than on RAD51C alone. Reason: Licenses the molecular function assigned to core function 1. That core function describes the RAD51-filament mediator role on RPA-coated ssDNA, and its supporting quotes are all ssDNA-context results with no four-way junction in them, so GO:0000400 (correct for core functions 2 and 3, which do rest on junction-binding specificity) was the wrong term there. The mediator activity itself has no GO molecular function - see proposed_new_terms. Supporting Evidence: PMID:11751636 Rad51B-Rad51C complex has ssDNA binding and ssDNA-stimulated ATPase activities |
| GO:0140664 ATP-dependent DNA damage sensor activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-derived electronic assignment of a damage-sensor activity. RAD51C does bind branched DNA and does have an ssDNA-stimulated ATPase, but the term denotes a molecule that "recognises toxic DNA structures, and initiates a signaling response, driven by ATP hydrolysis" - a sensor. RAD51C's demonstrated activity is loading RAD51 onto RPA-coated ssDNA; the CHK2 requirement is a downstream genetic dependency, not a demonstrated signal-initiating activity of RAD51C itself. Reason: Over-propagation of a RecA/RAD51-family ATPase/damage-sensor function, the same call the sibling XRCC2 review makes for the identical InterPro-derived row. It is not used by any core function here: the mediator activity it was standing in for has no GO term, and is filed under proposed_new_terms instead. The DNA-binding contributions RAD51C does make are carried by GO:0003697 and GO:0000400. Supporting Evidence: PMID:19451272 an early function of RAD51C in DNA repair in facilitating phosphorylation of the checkpoint kinase CHK2 |
| GO:0005515 protein binding | IPI PMID:11751635 Identification and purification of two distinct complexes co... | MARK AS OVER ANNOTATED | Summary: Captures interaction with RAD51B (BCDX2 subunit). Real interaction but the generic protein-binding term is uninformative about molecular function. Reason: Per curation guidelines, protein binding (GO:0005515) is uninformative as a molecular function. The specific, meaningful relationship (BCDX2 complex membership) is captured by GO:0033063 and the core functions. |
| GO:0005515 protein binding | IPI PMID:11842113 Involvement of Rad51C in two distinct protein complexes of R... | MARK AS OVER ANNOTATED | Summary: Captures paralog interactions (RAD51B/RAD51D/XRCC2/XRCC3). Uninformative MF term. Reason: Real interactions, but generic protein binding is uninformative; complex membership is captured by GO:0033063 and GO:0033065. |
| GO:0005515 protein binding | IPI PMID:16395335 Interplay between human DNA repair proteins at a unique doub... | MARK AS OVER ANNOTATED | Summary: Captures RAD51 interaction. Uninformative MF term. Reason: Interaction with RAD51 underlies the mediator function, which is better represented by the HR-mediator core functions rather than generic protein binding. |
| GO:0005515 protein binding | IPI PMID:21965664 hSWS1·SWSAP1 is an evolutionarily conserved complex required... | MARK AS OVER ANNOTATED | Summary: Captures SWSAP1 interaction (HR repair). Uninformative MF term. Reason: Generic protein binding is uninformative; interaction noted in the description. |
| GO:0005515 protein binding | IPI PMID:24005329 HELQ promotes RAD51 paralogue-dependent repair to avert germ... | MARK AS OVER ANNOTATED | Summary: Captures HELQ/XRCC3 interactions. Uninformative MF term. Reason: Generic protein binding is uninformative as a molecular function. |
| GO:0005515 protein binding | IPI PMID:24141787 Breast cancer-associated missense mutants of the PALB2 WD40 ... | MARK AS OVER ANNOTATED | Summary: Captures the PALB2/BRCA2/RAD51 HR-complex interactions. Real and important, but the generic term is uninformative. Reason: RAD51C is part of a PALB2-BRCA2-RAD51 HR complex; this is described in the gene summary but generic protein binding is not an informative molecular function. Supporting Evidence: PMID:24141787 part of a novel protein complex that contains PALB2 and BRCA2 |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome (XRCC3). Uninformative MF term. Reason: Generic protein binding from high-throughput data; uninformative. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome (XRCC2). Uninformative MF term. Reason: Generic protein binding from high-throughput data; uninformative. |
| GO:0005515 protein binding | IPI PMID:28864920 Discovery of mutations in homologous recombination genes in ... | MARK AS OVER ANNOTATED | Summary: Captures RAD51B/XRCC3 interactions. Uninformative MF term. Reason: Generic protein binding is uninformative as a molecular function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome (RAD51B/XRCC2/RAD51D). Uninformative MF term. Reason: Generic protein binding from proteome-scale data; uninformative. |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | MARK AS OVER ANNOTATED | Summary: Breast-cancer interactome (RAD51B/XRCC3). Uninformative MF term. Reason: Generic protein binding from high-throughput data; uninformative. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Multimodal cell-map interactome (RAD51B/RAD51D). Uninformative MF term. Reason: Generic protein binding from high-throughput data; uninformative. |
| GO:0005515 protein binding | IPI PMID:9469824 Isolation and characterization of RAD51C, a new human member... | MARK AS OVER ANNOTATED | Summary: Original yeast two-hybrid interactions with XRCC3 and RAD51B. Uninformative MF term. Reason: Historical two-hybrid interactions; generic protein binding is uninformative and the paralog relationships are captured by complex terms. Supporting Evidence: PMID:9469824 Rad51C protein binds to two other |
| GO:0000722 telomere maintenance via recombination | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: RAD51 paralogs contribute to recombination-based telomere maintenance (ALT). Inferred by orthology from mouse. Reason: Plausible peripheral role via the general HR machinery, but not a distinctively characterized core function of human RAD51C. Retained as non-core. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: RAD51C localizes to the nucleoplasm (immunofluorescence, HPA). Reason: Consistent with nuclear HR function; direct immunofluorescence evidence. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Mitochondrial localization (immunofluorescence, HPA), consistent with mtDNA role. Reason: Corroborates the experimentally demonstrated mitochondrial pool of RAD51C. Supporting Evidence: PMID:20413593 Rad51 and the related HR proteins Rad51C and Xrcc3 exist in human mitochondria |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosolic pool of RAD51C detected by immunofluorescence (HPA). Reason: Consistent with reported cytoplasmic/perinuclear pools regulating RAD51 stability. |
| GO:0000724 double-strand break repair via homologous recombination | NAS PMID:26354865 Mammalian RAD51 paralogs protect nascent DNA at stalled fork... | ACCEPT | Summary: RAD51C is required for HR repair of DNA double-strand breaks; this is its core biological process. Reason: Central, well-established function supported across many studies (mediator of RAD51 filament assembly required for HR). Supporting Evidence: PMID:37344587 BCDX2 stimulates the nucleation and extension of RAD51 |
| GO:0031297 replication fork processing | IDA PMID:26354865 Mammalian RAD51 paralogs protect nascent DNA at stalled fork... | ACCEPT | Summary: RAD51C protects nascent DNA at stalled forks and promotes replication restart in an ATP-hydrolysis-dependent manner. Reason: Directly demonstrated: RAD51C/XRCC3 prevent nascent-DNA degradation and restart halted forks; patient mutations abrogate fork protection. Supporting Evidence: PMID:26354865 RAD51C and XRCC3 promote the restart of stalled replication PMID:26354865 extensive degradation of nascent DNA at stalled |
| GO:0033065 Rad51C-XRCC3 complex | IPI PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: CX3 complex membership, established by co-purification with XRCC3. Reason: Core complex membership; direct biochemical evidence. Supporting Evidence: PMID:11751635 the five paralogs exist in two distinct complexes in human cells |
| GO:0043596 nuclear replication fork | IDA PMID:26354865 Mammalian RAD51 paralogs protect nascent DNA at stalled fork... | ACCEPT | Summary: RAD51C localizes to nuclear replication forks (nascent DNA) upon fork stalling. Reason: Directly demonstrated recruitment to stalled forks/nascent DNA. Supporting Evidence: PMID:26354865 extensive degradation of nascent DNA at stalled |
| GO:0005657 replication fork | NAS PMID:32669601 Sequential role of RAD51 paralog complexes in replication fo... | ACCEPT | Summary: RAD51C-containing paralog complexes act at replication forks during remodeling/restart. Reason: Consistent with fork localization and function; corroborated by EM and fork-protection studies. Supporting Evidence: PMID:32669601 RAD51 paralogs as important modulators of RAD51 foci formation upon mild replication stress |
| GO:0033063 Rad51B-Rad51C-Rad51D-XRCC2 complex | IPI PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: BCDX2 complex membership, established by co-purification. Reason: Core complex membership; direct biochemical evidence. Supporting Evidence: PMID:11751635 the five paralogs exist in two distinct complexes in human cells |
| GO:0097435 supramolecular fiber organization | IDA PMID:37344587 Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tum... | MODIFY | Summary: As part of BCDX2, RAD51C promotes nucleation and extension of the RAD51 nucleoprotein filament (a supramolecular fiber) in an ATP-hydrolysis-dependent manner. This captures the core mediator function. Reason: Directly demonstrated by cryo-EM and single-molecule assays that BCDX2 stimulates RAD51 filament nucleation/extension via coupled RAD51B/RAD51C ATPases, but supramolecular fiber organization is a generic parent. GO:0000730 DNA recombinase assembly - "the aggregation, arrangement and bonding together of strand exchange proteins (recombinases) into higher order oligomers on single-stranded DNA" - is literally what this experiment shows, and is the term this same PR uses for RAD51. The generic supramolecular-fiber parent loses the recombinase identity, which is the whole content of the finding. Proposed replacements: DNA recombinase assembly Supporting Evidence: PMID:37344587 BCDX2 stimulates the nucleation and extension of RAD51 PMID:37344587 BCDX2 promotes RAD51 filament nucleation and growth in an ATP hydrolysis dependent manner |
| GO:0005515 protein binding | IPI PMID:35849344 LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damag... | MARK AS OVER ANNOTATED | Summary: Captures interaction with the DDUP microprotein in the DNA damage response. Uninformative MF term. Reason: Generic protein binding is uninformative as a molecular function. |
| GO:0000400 four-way junction DNA binding | IDA PMID:20207730 Ring-shaped Rad51 paralog protein complexes bind Holliday ju... | ACCEPT | Summary: Direct EM demonstration that BCDX2 and CX3 bind four-way (Holliday) junctions with high specificity. Reason: Strong experimental support; contributes_to reflects that binding is a property of the assembled complex. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally high specificity to the DNA junctions PMID:20207730 revealed a multimeric ring structure whose subunits are arranged into a flat disc around a central channel |
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:23149936 Rad51 paralog complexes BCDX2 and CX3 act at different stage... | ACCEPT | Summary: RAD51C (in BCDX2 and CX3) is required for HR at defined steps: BCDX2 downstream of BRCA2 and upstream of RAD51 loading, CX3 downstream of RAD51. Reason: Experimental epistasis analysis places both RAD51C complexes within the BRCA-dependent HR pathway. Core function. Supporting Evidence: PMID:23149936 act at different stages of the HR pathway PMID:23149936 the BCDX2 complex acts downstream of BRCA2 recruitment but |
| GO:0005657 replication fork | IDA PMID:20207730 Ring-shaped Rad51 paralog protein complexes bind Holliday ju... | ACCEPT | Summary: BCDX2/CX3 bind replication-fork DNA (direct EM visualization). Reason: Directly demonstrated binding to forked DNA templates. Supporting Evidence: PMID:20207730 binding of BCDX2 and CX3 to DNA templates containing replication forks and |
| GO:0008821 crossover junction DNA endonuclease activity | IMP PMID:14716019 RAD51C is required for Holliday junction processing in mamma... | MARK AS OVER ANNOTATED | Summary: RAD51C depletion reduces Holliday-junction branch migration and resolvase activity in human extracts, but RAD51C is a RecA-fold ATPase mediator with no nuclease active site; the resolvase catalysis is contributed by GEN1, not RAD51C. Reason: The experimental result (PMID:14716019) shows RAD51C is required for HJ processing activity in extracts, which the annotation reasonably reflects with contributes_to. However, subsequent work assigned the actual endonucleolytic resolution to GEN1 (acting with XRCC3); RAD51C promotes branch migration/resolution without possessing endonuclease activity itself. Attributing this catalytic molecular function to RAD51C is an over-annotation. Not removed, since the paper's experimental support is genuine. Supporting Evidence: PMID:14716019 depletion of RAD51C from PMID:14716019 caused a loss of branch migration and PMID:23108668 XRCC3 functions jointly with GEN1 later |
| GO:0010971 positive regulation of G2/M transition of mitotic cell cycle | IMP PMID:23108668 The RAD51 paralogs ensure cellular protection against mitoti... | KEEP AS NON CORE | Summary: RAD51B/RAD51C depletion induces G2/M arrest; RAD51C normally supports mitotic progression by completing recombinational repair and protecting against mitotic defects/aneuploidy. Reason: Experimentally supported (IMP), but this cell-cycle effect is largely a downstream consequence of RAD51C's HR/repair role rather than a distinct core molecular function. Retained as non-core. Supporting Evidence: PMID:23108668 inhibition of RAD51B or RAD51C induces |
| GO:0033063 Rad51B-Rad51C-Rad51D-XRCC2 complex | IDA PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: BCDX2 complex membership (direct isolation/purification). Reason: Core complex membership; direct experimental evidence. Supporting Evidence: PMID:11751635 the five paralogs exist in two distinct complexes in human cells |
| GO:0033065 Rad51C-XRCC3 complex | IDA PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: CX3 complex membership (direct isolation/purification). Reason: Core complex membership; direct experimental evidence. Supporting Evidence: PMID:11751635 the five paralogs exist in two distinct complexes in human cells |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685318 | ACCEPT | Summary: Nucleoplasmic localization (Reactome, BCDX2 complex formation). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685319 | ACCEPT | Summary: Nucleoplasmic localization (Reactome, CX3 complex formation). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685341 | ACCEPT | Summary: Nucleoplasmic localization (Reactome, BCDX2 stabilizes RAD51 filament). Reason: Consistent with nuclear HR mediator function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685838 | ACCEPT | Summary: Nucleoplasmic localization (Reactome, CX3 binds D-loop structures). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686410 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686440 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686469 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686483 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693539 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693584 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693589 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693593 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693620 | ACCEPT | Summary: Nucleoplasmic localization (Reactome, D-loop formation by PALB2/BRCA2/RAD51). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9701199 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704330 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704408 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9709601 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-983218 | ACCEPT | Summary: Nucleoplasmic localization (Reactome, RAD51B:RAD51C binds ssDNA). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-983285 | ACCEPT | Summary: Nucleoplasmic localization (Reactome, RAD51B binds RAD51C). Reason: Consistent with nuclear HR function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9853389 | ACCEPT | Summary: Nucleoplasmic localization (Reactome HR pathway step). Reason: Consistent with nuclear HR function. |
| GO:0007062 sister chromatid cohesion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: RAD51C contributes to sister chromatid cohesion (UniProt), inferred by sequence similarity from mouse ortholog and directly supported by hamster RAD51C-mutant (CL-V4B) cells. Reason: A reported contributory role but peripheral to the core HR-mediator function; kept as non-core. Experimentally corroborated: RAD51C-deficient CL-V4B cells show reduced sister chromatid cohesion, complemented by Rad51C cDNA. Supporting Evidence: PMID:12000837 reduced level of sister chromatid cohesion was found in CL-V4B cells |
| GO:0005634 nucleus | IDA PMID:12966089 Identification of functional domains in the RAD51L2 (RAD51C)... | ACCEPT | Summary: GFP-tagged RAD51L2/RAD51C localizes to the nucleus; a C-terminal NLS is identified. Reason: Direct experimental localization to the nucleus. Supporting Evidence: PMID:12966089 the protein is localized |
| GO:0005634 nucleus | IDA PMID:16215984 Cellular localization of human Rad51C and regulation of ubiq... | ACCEPT | Summary: Endogenous RAD51C detected in the nucleus; nuclear levels increase after DNA damage. Reason: Direct experimental localization. Supporting Evidence: PMID:16215984 detect endogenous Rad51C |
| GO:0005737 cytoplasm | IDA PMID:16215984 Cellular localization of human Rad51C and regulation of ubiq... | ACCEPT | Summary: Endogenous RAD51C detected in the cytoplasm; regulates RAD51 proteolysis. Reason: Directly demonstrated cytoplasmic pool. Supporting Evidence: PMID:16215984 important role in regulating this process |
| GO:0006281 DNA repair | IDA PMID:19451272 RAD51C facilitates checkpoint signaling by promoting CHK2 ph... | ACCEPT | Summary: RAD51C has an early DNA-repair function facilitating CHK2 phosphorylation and damage-signal transduction leading to cell-cycle arrest and HR activation. Reason: Direct experimental evidence for a DNA-repair/damage-response function of RAD51C. Supporting Evidence: PMID:19451272 an early function of RAD51C in DNA repair in facilitating phosphorylation of the checkpoint kinase CHK2 |
| GO:0000077 DNA damage checkpoint signaling | IMP PMID:19451272 RAD51C facilitates checkpoint signaling by promoting CHK2 ph... | NEW | Summary: Proposed new annotation. RAD51C accumulates at DNA-damage sites (ATM-, NBS1- and RPA-dependent) and is required for phosphorylation of the checkpoint kinase CHK2, transducing the damage signal that enforces S and G2/M arrest. GOA captures this only as the generic GO:0006281 DNA repair, which does not describe checkpoint transduction. Reason: Checkpoint signalling is a distinct process from the repair reaction itself, and the same reference that supports the GO:0006281 row demonstrates the CHK2 arm specifically. Added so that the corresponding core function has a process term that matches what it describes; FANCM in this same cohort already carries GO:0000077 for equivalent evidence, and with the same code. Evidence is IMP, not IDA: the CHK2 result rests on siRNA depletion of RAD51C ("cells depleted of RAD51C"), which is a mutant/altered-gene-product phenotype. GOA codes its GO:0006281 row on this PMID as IDA, but that is a curator's choice and not one to restate as our own on an author-supplied annotation. Supporting Evidence: PMID:19451272 an early function of RAD51C in DNA repair in facilitating phosphorylation of the checkpoint kinase CHK2 |
| GO:0006310 DNA recombination | IDA PMID:19451272 RAD51C facilitates checkpoint signaling by promoting CHK2 ph... | ACCEPT | Summary: RAD51C acts in the homologous recombination pathway, accumulating at damage sites with an early and late role. Reason: Supported by RAD51C's recruitment kinetics and mediator role in HR; DNA recombination is an accurate parent term. Supporting Evidence: PMID:19451272 The kinetics of RAD51C recruitment is consistent with both an early and a late role in HR |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16215984 Cellular localization of human Rad51C and regulation of ubiq... | KEEP AS NON CORE | Summary: RAD51C is detected in a perinuclear cytoplasmic region. Reason: Supported peripheral localization, not part of the core nuclear HR-mediator function. Supporting Evidence: PMID:16215984 detect endogenous Rad51C |
| GO:0005739 mitochondrion | IDA PMID:20413593 Discovery of a novel function for human Rad51: maintenance o... | ACCEPT | Summary: RAD51C is present in human mitochondria and maintains mtDNA copy number under oxidative stress (with RAD51 and XRCC3). Reason: Directly demonstrated mitochondrial localization and function. Supporting Evidence: PMID:20413593 Depletion of Rad51, Rad51C, or Xrcc3 results in a dramatic decrease in mtDNA copy number |
| GO:0003677 DNA binding | TAS PMID:9469824 Isolation and characterization of RAD51C, a new human member... | ACCEPT | Summary: RAD51C is a RAD51-family strand-exchange-related protein reported to bind DNA; the complexes it forms bind ssDNA/branched/duplex DNA. Reason: Accurate broad molecular function; corroborated by biochemical DNA-binding of BCDX2/CX3. Supporting Evidence: PMID:9469824 recombinational repair of DNA damage and meiotic |
| GO:0005634 nucleus | TAS PMID:9469824 Isolation and characterization of RAD51C, a new human member... | ACCEPT | Summary: RAD51C is a nuclear DNA-repair/recombination protein. Reason: Consistent with all subsequent localization data. |
| GO:0006281 DNA repair | TAS PMID:9469824 Isolation and characterization of RAD51C, a new human member... | ACCEPT | Summary: RAD51C functions in recombinational repair of DNA damage. Reason: Accurate broad DNA-repair role; well supported by the whole literature. Supporting Evidence: PMID:9469824 recombinational repair of DNA damage and meiotic |
| GO:0006310 DNA recombination | TAS PMID:9469824 Isolation and characterization of RAD51C, a new human member... | ACCEPT | Summary: RAD51C is a member of the RAD51 recombination family involved in DNA recombination. Reason: Accurate broad recombination role. Supporting Evidence: PMID:9469824 recombinational repair of DNA damage and meiotic |
| GO:0036297 interstrand cross-link repair | IMP PMID:20400963 Mutation of the RAD51C gene in a Fanconi anemia-like disorde... | NEW | Summary: RAD51C is the Fanconi anemia complementation group O (FANCO) gene; biallelic loss of function causes an FA-like disorder with hypersensitivity to DNA interstrand cross-linking agents (mitomycin C, cisplatin). RAD51C acts downstream in the ICL-repair pathway (via homologous recombination), not in ICL unhooking or FANCD2 monoubiquitination. This specific process is only captured broadly by DNA repair / DSB-repair-via-HR in the existing GOA set. Reason: Interstrand cross-link repair is a core, defining, well-evidenced function of RAD51C (FANCO): patient/mutant cells are hypersensitive to ICL agents and biallelic mutation causes a Fanconi anemia-like syndrome. GO:0036297 is the appropriate specific biological process term (active BP, verified via QuickGO), more precise than the existing GO:0006281 DNA repair parent. Supporting Evidence: PMID:20400963 increased cellular sensitivity to the DNA interstrand cross-linking agent mitomycin C and the topoisomerase-1 inhibitor camptothecin PMID:20400963 biallelic germline mutations in a RAD51 paralog are associated with an FA-like syndrome |
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Download this section (compressed HTML)Q: Does RAD51C possess intrinsic catalytic activity beyond ATP hydrolysis, or is its function entirely as a DNA-binding, RAD51-filament mediator within BCDX2 and CX3?
Q: What is the mechanistic basis by which RAD51C is required for CHK2 activation - a direct scaffolding role at damage sites or an indirect consequence of HR intermediate processing?
Experiment: Structure-guided separation-of-function mutants that uncouple RAD51C ssDNA binding, ATP hydrolysis, and RAD51-filament stimulation, tested for HR, fork protection, and checkpoint signaling.
Experiment: Reconstituted assays with purified CX3 to define whether RAD51C/XRCC3 directly drive branch migration independently of GEN1-mediated junction cleavage.
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