XRCC3 (X-ray repair cross-complementing protein 3) is one of the five human RAD51 paralogs, a RecA/RAD51-family protein with an N-terminal domain and a C-terminal Walker A/B ATPase domain. All of its characterized activities are exerted as the obligate partner of RAD51C in the CX3 (RAD51C-XRCC3) heterodimer, and CX3 also assembles with RAD51D-XRCC2 into the X3CDX2 (DX2-CX3) tetramer, with RAD51 into an autoinhibited RAD51-X3C octamer, and with BCDX2 into a BCDX2-CX3-RAD51 supercomplex. Within these assemblies XRCC3 contacts RAD51 directly; X3CDX2 caps the 5' end of RAD51-ssDNA filaments (XRCC2 forming the cap) and stabilizes them, and XRCC3-containing complexes stimulate RAD51-mediated strand exchange and D-loop formation. CX3 binds Holliday junctions and fork junctions, acts downstream of RAD51 recruitment in BRCA1-BRCA2-dependent homologous recombination, and influences late steps of recombination, including gene-conversion tract length and GEN1-associated Holliday junction resolution in mitotic cells. During replication stress XRCC3 associates with nascent DNA at stalled forks, contributes to protection of nascent strands, and, uniquely among the paralog complexes, promotes ATP-hydrolysis-dependent restart of stalled and collapsed forks; ATM/ATR phosphorylation of XRCC3 Ser225 is required for RAD51 chromatin loading, HR repair and recovery of collapsed (but not stalled) forks. CX3 also recruits the FANCM translocase to R-loops to suppress transcription-replication conflicts. XRCC3 participates in recombination-mediated telomere trimming (t-loop deletion / t-circle formation) and is found in mitochondria, where RAD51C/XRCC3 associates with the nucleoid and supports mtDNA replication and copy number. XRCC3-deficient cells are hypersensitive to DNA cross-linking agents and ionizing radiation and are chromosomally unstable; germline variants are associated with breast cancer susceptibility.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000400 four-way junction DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Four-way (Holliday) junction DNA binding by the RAD51C-XRCC3 (CX3) complex; contributes_to is appropriate because binding is measured on the complex. Reason: Purified CX3 binds Holliday junctions and fork junctions with high specificity (EM). The phylogenetic inference is consistent with the direct evidence on human XRCC3. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally high specificity to the DNA junctions |
| GO:0000400 four-way junction DNA binding | IDA PMID:20207730 Ring-shaped Rad51 paralog protein complexes bind Holliday ju... | ACCEPT | Summary: EM of purified human CX3 shows high-specificity binding at the junction of Holliday-junction and replication-fork DNA templates. Reason: Direct biochemical evidence; contributes_to correctly captures that the activity was measured on the RAD51C-XRCC3 heterodimer. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally high specificity to the DNA junctions |
| GO:0000722 telomere maintenance via recombination | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: XRCC3 participates in homologous-recombination events at telomeres (t-loop deletion / t-circle formation). Reason: XRCC3-dependent telomeric recombination is experimentally supported in human cells (t-loop HR deletion, telomere trimming), but it is a context-specific deployment of its general HR mediator role rather than a core function. Supporting Evidence: PMID:15507207 TRF2DeltaB-induced deletions depended on XRCC3, a protein implicated in Holliday junction resolution, and created t-loop-sized telomeric circles |
| GO:0000722 telomere maintenance via recombination | IMP PMID:15507207 Homologous recombination generates T-loop-sized deletions at... | KEEP AS NON CORE | Summary: TRF2-deltaB-induced catastrophic telomere deletions generating t-loop-sized telomeric circles depend on XRCC3. Reason: Valid experimental evidence of XRCC3-dependent telomeric HR; non-core because it reflects the general HR machinery acting at telomeres (and this process actually shortens telomeres). Supporting Evidence: PMID:15507207 TRF2DeltaB-induced deletions depended on XRCC3, a protein implicated in Holliday junction resolution, and created t-loop-sized telomeric circles |
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:23149936 Rad51 paralog complexes BCDX2 and CX3 act at different stage... | ACCEPT | Summary: Epistasis places CX3 downstream of RAD51 recruitment in the BRCA1-BRCA2-dependent HR pathway, with a marked effect on HR frequency. Reason: Core function. XRCC3 deficiency reduces DSB-induced HR; structural/biochemical studies now show the CX3/X3CDX2 complexes engage RAD51 filaments and stimulate strand exchange, providing a mechanism for this role. Supporting Evidence: PMID:23149936 the CX3 complex acts downstream of Rad51 recruitment but still has a marked impact on the measured frequency of homologous recombination PMID:23438602 XRCC3 phosphorylation is required for chromatin loading of RAD51 and HR-mediated repair of double-strand breaks |
| GO:0000724 double-strand break repair via homologous recombination | NAS PMID:26354865 Mammalian RAD51 paralogs protect nascent DNA at stalled fork... | ACCEPT | Summary: ComplexPortal statement that the CX3 complex functions in HR repair of DSBs. Reason: Consistent with extensive experimental evidence on XRCC3 in HR (see IMP annotation from PMID:23149936). Supporting Evidence: PMID:23149936 the CX3 complex acts downstream of Rad51 recruitment but still has a marked impact on the measured frequency of homologous recombination |
| GO:0000781 chromosome, telomeric region | IC PMID:15507207 Homologous recombination generates T-loop-sized deletions at... | KEEP AS NON CORE | Summary: Telomeric localization inferred by curator from the telomere HR process annotation. Reason: Reasonable inference given XRCC3-dependent telomeric recombination, but XRCC3 has no telomere-specific localization mechanism; peripheral to its function. Supporting Evidence: PMID:15507207 TRF2DeltaB-induced deletions depended on XRCC3, a protein implicated in Holliday junction resolution, and created t-loop-sized telomeric circles |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: DNA binding inferred from the RecA ATP-binding domain (InterPro). Reason: Correct though general; CX3 binds ssDNA and branched DNA, and cryo-EM shows CX3 engaging ssDNA within paralog-RAD51 assemblies. More specific junction binding is captured by GO:0000400. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally high specificity to the DNA junctions |
| GO:0005515 protein binding | IPI PMID:11751635 Identification and purification of two distinct complexes co... | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:11751635). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:11842113 Involvement of Rad51C in two distinct protein complexes of R... | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:11842113). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:11842113 Involvement of Rad51C in two distinct protein complexes of R... | REMOVE | Summary: IPI protein binding with RAD51 (PMID:11842113). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:21965664 hSWS1Β·SWSAP1 is an evolutionarily conserved complex required... | REMOVE | Summary: IPI protein binding with SWSAP1 (PMID:21965664). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:24005329 HELQ promotes RAD51 paralogue-dependent repair to avert germ... | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:24005329). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:24141787 Breast cancer-associated missense mutants of the PALB2 WD40 ... | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:24141787). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:24141787 Breast cancer-associated missense mutants of the PALB2 WD40 ... | REMOVE | Summary: IPI protein binding with PALB2 (PMID:24141787). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:26496610). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:28864920 Discovery of mutations in homologous recombination genes in ... | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:28864920). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:28864920 Discovery of mutations in homologous recombination genes in ... | REMOVE | Summary: IPI protein binding with RAD51 (PMID:28864920). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:34591612). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:9469824 Isolation and characterization of RAD51C, a new human member... | REMOVE | Summary: IPI protein binding with RAD51C (CX3 partner) (PMID:9469824). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005515 protein binding | IPI PMID:9660962 XRCC2 and XRCC3, new human Rad51-family members, promote chr... | REMOVE | Summary: IPI protein binding with RAD51 (PMID:9660962). Reason: GO:0005515 protein binding is uninformative about XRCC3 function and is removed per project policy for generic protein-binding annotations; removal does not dispute the reported interaction. The biologically meaningful content is captured elsewhere: the RAD51C interaction by GO:0033065 Rad51C-XRCC3 complex, and the direct RAD51 interaction by the proposed contributes_to GO:0140619 DNA strand exchange activator activity (CX3/X3CDX2 engages RAD51 and stimulates its strand exchange). |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding via the conserved Walker A motif of the RecA-like ATPase domain. Reason: XRCC3 retains Walker A/B motifs; ATP binding and hydrolysis-defective XRCC3 mutants are defective in replication restart. Supporting Evidence: PMID:26354865 However, RAD51C and XRCC3 mediated ATP hydrolysis was found to be critical for restart |
| GO:0005634 nucleus | IDA PMID:16215984 Cellular localization of human Rad51C and regulation of ubiq... | ACCEPT | Summary: Endogenous XRCC3 detected in the nucleus by immunofluorescence. Reason: Nuclear localization is consistent with XRCC3's HR and replication functions. Supporting Evidence: PMID:16215984 we are able to detect endogenous Rad51C and Xrcc3 in human cells |
| GO:0005634 nucleus | IDA PMID:26323318 NUCKS1 is a novel RAD51AP1 paralog important for homologous ... | ACCEPT | Summary: XRCC3 detected in soluble nuclear and chromatin fractions in the NUCKS1 study. Reason: Consistent with nuclear localization; the study fractionated nuclei of XRCC3-depleted and control HeLa cells. Supporting Evidence: PMID:26323318 NUCKS1- and/or XRCC3-depleted HeLa cells show similarly increased cellular sensitivity to MMC treatment compared to control transfected cells |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (Nucleus). Reason: Consistent with experimental data. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence localizes XRCC3 to the nucleoplasm. Reason: Consistent with nuclear HR/replication functions. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685319 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685838 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686410 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686440 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686469 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686483 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693539 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693584 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693589 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693593 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9853389 | ACCEPT | Summary: Reactome places the CX3 (RAD51C-XRCC3) complex in the nucleoplasm in its homologous recombination reactions (D-loop binding, Holliday junction processing, FIGNL1-RAD51). Nucleoplasmic localization of XRCC3 is consistent with experimental data. Reason: Correct and consistent with nuclear localization of XRCC3 and the CX3 complex. |
| GO:0005657 replication fork | IBA GO_REF:0000033 | ACCEPT | Summary: RAD51 paralogs, including XRCC3, act at replication forks. Reason: XRCC3 localizes to nascent DNA at stalled forks and is required for fork restart; the phylogenetic inference is well grounded in human data. Supporting Evidence: PMID:26354865 We show that RAD51 paralogs localize to nascent DNA and common fragile sites upon replication fork stalling PMID:26354865 RAD51C and XRCC3 promote the restart of stalled replication in an ATP hydrolysis dependent manner |
| GO:0005657 replication fork | IDA PMID:20207730 Ring-shaped Rad51 paralog protein complexes bind Holliday ju... | ACCEPT | Summary: EM shows CX3 binding to replication-fork DNA templates in vitro. Reason: The cited evidence is in vitro binding to fork-shaped DNA rather than cellular localization, but in-cell localization of XRCC3 to nascent DNA at stalled forks (PMID:26354865) independently supports the term. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally high specificity to the DNA junctions PMID:26354865 We show that RAD51 paralogs localize to nascent DNA and common fragile sites upon replication fork stalling |
| GO:0005694 chromosome | IEA GO_REF:0000117 | ACCEPT | Summary: Chromosome localization (ARBA rule). Reason: XRCC3 is chromatin-associated (RAD51 loading, nascent DNA at forks); correct though general. |
| GO:0005737 cytoplasm | IDA PMID:16215984 Cellular localization of human Rad51C and regulation of ubiq... | KEEP AS NON CORE | Summary: Endogenous XRCC3 detected in the cytoplasm. Reason: Cytoplasmic pool is reported, plausibly reflecting synthesis/transit and mitochondrial import; not where its core functions are executed. Supporting Evidence: PMID:16215984 we are able to detect endogenous Rad51C and Xrcc3 in human cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping (Cytoplasm). Reason: As for the IDA annotation; correct but peripheral. |
| GO:0005739 mitochondrion | IDA PMID:20413593 Discovery of a novel function for human Rad51: maintenance o... | ACCEPT | Summary: XRCC3 (with RAD51 and RAD51C) is present in mitochondria of human cells, increasing after oxidative stress. Reason: Directly demonstrated by fractionation; corroborated by later work showing RAD51C/XRCC3 in the mitochondrial nucleoid. Supporting Evidence: PMID:20413593 Here, we provide the first demonstration that Rad51 and the related HR proteins Rad51C and Xrcc3 exist in human mitochondria PMID:29158291 RAD51C/XRCC3 is an additional component of the mitochondrial nucleoid having nucleus-independent roles in mtDNA maintenance |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (Mitochondrion). Reason: Consistent with experimental data. Supporting Evidence: PMID:20413593 Here, we provide the first demonstration that Rad51 and the related HR proteins Rad51C and Xrcc3 exist in human mitochondria |
| GO:0006281 DNA repair | IEA GO_REF:0000002 | ACCEPT | Summary: DNA repair inferred from RecA-family domain. Reason: Correct; more specific HR terms are also annotated. |
| GO:0006281 DNA repair | IGI PMID:10422536 The XRCC2 and XRCC3 repair genes are required for chromosome... | ACCEPT | Summary: Microcell transfer of human chromosome 14 (carrying XRCC3) corrects MMC sensitivity and chromosome instability of XRCC3-mutant irs1SF cells. Reason: Classic genetic evidence for XRCC3 in DNA repair; general term. Supporting Evidence: PMID:10422536 the XRCC2 and XRCC3 genes, which are now considered members of the RAD51 gene family, play essential roles in maintaining chromosome stability during cell division |
| GO:0006281 DNA repair | TAS PMID:9660962 XRCC2 and XRCC3, new human Rad51-family members, promote chr... | ACCEPT | Summary: XRCC3 complements irs1SF cross-linker sensitivity and is a RAD51-family member. Reason: Correct, general. Supporting Evidence: PMID:9660962 XRCC3 is shown to interact directly with HsRad51 |
| GO:0006302 double-strand break repair | IEA GO_REF:0000117 | ACCEPT | Summary: Double-strand break repair (ARBA). Reason: Correct; XRCC3 functions in DSB repair by HR. |
| GO:0006310 DNA recombination | TAS PMID:9660962 XRCC2 and XRCC3, new human Rad51-family members, promote chr... | ACCEPT | Summary: XRCC3 implicated in homologous recombination as a RAD51-family member interacting with RAD51. Reason: Correct, general. Supporting Evidence: PMID:9660962 XRCC3 is shown to interact directly with HsRad51 |
| GO:0006974 DNA damage response | TAS PMID:7603995 Correction of chromosomal instability and sensitivity to div... | ACCEPT | Summary: XRCC3 cDNA corrects mutagen sensitivity and chromosomal instability of irs1SF cells. Reason: Correct but very general; more informative repair terms are present. Supporting Evidence: PMID:7603995 Transformants also showed partial correction of sensitivity to cisplatin and gamma-rays, efficient correction of chromosomal instability |
| GO:0008821 crossover junction DNA endonuclease activity | IMP PMID:14716019 RAD51C is required for Holliday junction processing in mamma... | MARK AS OVER ANNOTATED | Summary: Extracts of XRCC3- or RAD51C-mutant cells have reduced Holliday junction resolvase activity. Reason: XRCC3 is a RecA-fold ATPase with no nuclease motif; the reduced resolvase activity in mutant extracts shows involvement in junction processing, not that XRCC3 (or CX3) contributes catalytic endonuclease activity. Junction cleavage was later attributed to GEN1 acting with XRCC3. The process role is captured by GO:0071140. Consistent with the sibling RAD51C review. Supporting Evidence: PMID:14716019 extracts from cells carrying mutations in the recombination/repair genes RAD51C or XRCC3 have reduced levels of HJ resolvase activity PMID:23108668 XRCC3 functions jointly with GEN1 later in the pathway at the stage of Holliday junction resolution |
| GO:0008821 crossover junction DNA endonuclease activity | IMP PMID:23108668 The RAD51 paralogs ensure cellular protection against mitoti... | MARK AS OVER ANNOTATED | Summary: XRCC3 acts jointly with GEN1 at the Holliday junction resolution stage. Reason: GEN1 is the catalytic resolvase; XRCC3 participates in the resolution process but does not contribute endonuclease activity. Process role retained via GO:0071140. Supporting Evidence: PMID:23108668 XRCC3 functions jointly with GEN1 later in the pathway at the stage of Holliday junction resolution |
| GO:0010824 regulation of centrosome duplication | IMP PMID:23108668 The RAD51 paralogs ensure cellular protection against mitoti... | MARK AS OVER ANNOTATED | Summary: XRCC3 knockdown causes centrosome defects alongside chromosome misalignment, anaphase bridges and aneuploidy. Reason: Centrosome defects in XRCC3-deficient cells are most parsimoniously an indirect consequence of unresolved recombination intermediates/DNA damage (as concluded for XRCC2/XRCC3-deficient hamster cells), not evidence that XRCC3 regulates centrosome duplication. Full text not available to us; not removed. Supporting Evidence: PMID:11025669 Our results show that unresolved DNA damage triggers this instability PMID:23108668 XRCC3 functions jointly with GEN1 later in the pathway at the stage of Holliday junction resolution |
| GO:0031297 replication fork processing | IDA PMID:26354865 Mammalian RAD51 paralogs protect nascent DNA at stalled fork... | ACCEPT | Summary: XRCC3 localizes to stalled forks, protects nascent DNA and, with RAD51C, promotes ATP-hydrolysis-dependent restart of stalled replication. Reason: Core function. Restart of stalled/collapsed forks is a CX3-specific function not shared by BCDX2 (XRCC2 dispensable), as summarized in the trigger review. Supporting Evidence: PMID:26354865 RAD51C and XRCC3 promote the restart of stalled replication in an ATP hydrolysis dependent manner PMID:26354865 Interestingly, unlike RAD51C and XRCC3, XRCC2 was dispensable for replication restart PMID:42682019 only the CX3 complex participates in restarting stalled/collapsed replication forks, marking a separation of function between the two paralog complexes |
| GO:0033065 Rad51C-XRCC3 complex | IBA GO_REF:0000033 | ACCEPT | Summary: XRCC3 is the RAD51C partner in the CX3 heterodimer. Reason: Directly demonstrated by complex purification; conserved. Supporting Evidence: PMID:11751635 the other consists of RAD51C with XRCC3 |
| GO:0033065 Rad51C-XRCC3 complex | IDA PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: Purification of the RAD51C-XRCC3 complex from human cells. Reason: Primary evidence for CX3 complex membership. Supporting Evidence: PMID:11751635 the other consists of RAD51C with XRCC3 |
| GO:0033065 Rad51C-XRCC3 complex | IPI PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: Co-purification of RAD51C with XRCC3. Reason: Primary evidence for CX3 complex membership. Supporting Evidence: PMID:11751635 the other consists of RAD51C with XRCC3 |
| GO:0036297 interstrand cross-link repair | IMP PMID:26323318 NUCKS1 is a novel RAD51AP1 paralog important for homologous ... | ACCEPT | Summary: XRCC3-depleted HeLa cells are hypersensitive to MMC, epistatic with NUCKS1. Reason: Cross-link hypersensitivity is the defining phenotype of XRCC3-mutant cells (irs1SF) and HR-mediated repair of ICL-induced breaks is a well-established XRCC3 role. Supporting Evidence: PMID:26323318 NUCKS1- and/or XRCC3-depleted HeLa cells show similarly increased cellular sensitivity to MMC treatment compared to control transfected cells PMID:7603995 Transformants also showed partial correction of sensitivity to cisplatin and gamma-rays, efficient correction of chromosomal instability |
| GO:0043596 nuclear replication fork | IDA PMID:26354865 Mammalian RAD51 paralogs protect nascent DNA at stalled fork... | ACCEPT | Summary: XRCC3 associates with nascent DNA at stalled nuclear replication forks. Reason: Directly supported. Supporting Evidence: PMID:26354865 We show that RAD51 paralogs localize to nascent DNA and common fragile sites upon replication fork stalling |
| GO:0045003 double-strand break repair via synthesis-dependent strand annealing | IBA GO_REF:0000033 | ACCEPT | Summary: DSB repair via synthesis-dependent strand annealing, propagated from plant XRCC3. Reason: SDSA is the predominant non-crossover HR outcome in somatic cells; human XRCC3 mutants show altered gene-conversion tract lengths and aberrant processing of HR intermediates, consistent with a conserved role in this HR sub-pathway. The IBA node placement is not contradicted by human data. Supporting Evidence: PMID:12191483 XRCC3 function is not limited to HR initiation, but extends to later stages in formation and resolution of HR intermediates |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16215984 Cellular localization of human Rad51C and regulation of ubiq... | KEEP AS NON CORE | Summary: Perinuclear XRCC3 staining. Reason: Reported localization, not linked to a known function. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping (perinuclear region). Reason: As for IDA. |
| GO:0071140 resolution of mitotic recombination intermediates | IBA GO_REF:0000033 | ACCEPT | Summary: XRCC3 participates in processing/resolution of mitotic recombination intermediates (Holliday junctions). Reason: Supported by XRCC3-dependent HJ resolvase activity in extracts, the GEN1-XRCC3 epistasis in mitotic cells, altered HR product spectra in XRCC3 mutants, and CX3 junction binding. XRCC3 is not the nuclease; the term is a process term and its participation (junction binding/processing) is appropriate. Supporting Evidence: PMID:12191483 XRCC3 function is not limited to HR initiation, but extends to later stages in formation and resolution of HR intermediates PMID:23108668 XRCC3 functions jointly with GEN1 later in the pathway at the stage of Holliday junction resolution PMID:14716019 extracts from cells carrying mutations in the recombination/repair genes RAD51C or XRCC3 have reduced levels of HJ resolvase activity |
| GO:0071140 resolution of mitotic recombination intermediates | IMP PMID:23108668 The RAD51 paralogs ensure cellular protection against mitoti... | ACCEPT | Summary: XRCC3 acts with GEN1 at the HJ resolution stage in mitotic cells. Reason: Direct experimental support (knockdown/epistasis); see IBA review. Supporting Evidence: PMID:23108668 XRCC3 functions jointly with GEN1 later in the pathway at the stage of Holliday junction resolution |
| GO:0090267 positive regulation of mitotic cell cycle spindle assembly checkpoint | IMP PMID:23108668 The RAD51 paralogs ensure cellular protection against mitoti... | MARK AS OVER ANNOTATED | Summary: XRCC3 knockdown leads to persistent spindle assembly checkpoint, chromosome misalignment and aneuploidy. Reason: The phenotype (persistent SAC after XRCC3 loss) is an indirect consequence of unresolved Holliday junctions/anaphase bridges rather than XRCC3 acting as a regulator of the checkpoint; the direction implied by 'positive regulation' is also not evident from the abstract. Full text unavailable to us, so not removed. Supporting Evidence: PMID:23108668 Our data demonstrate that Holliday junction resolution has critical functions for preventing aberrant mitosis and aneuploidy in mitotic cells |
| GO:0090656 t-circle formation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: t-circle formation by XRCC3-dependent HR at telomeres. Reason: Experimentally supported in human cells; telomere-specific deployment of HR. Supporting Evidence: PMID:21903669 the mechanism involves the XRCC3 homologous recombination (HR) protein and generates single-stranded C-rich telomeric DNA |
| GO:0090656 t-circle formation | IC PMID:15507207 Homologous recombination generates T-loop-sized deletions at... | KEEP AS NON CORE | Summary: Curator inference of t-circle formation from XRCC3-dependent t-loop-sized circle generation. Reason: Supported; non-core. Supporting Evidence: PMID:15507207 TRF2DeltaB-induced deletions depended on XRCC3, a protein implicated in Holliday junction resolution, and created t-loop-sized telomeric circles |
| GO:0090656 t-circle formation | IMP PMID:21903669 Normal mammalian cells negatively regulate telomere length b... | KEEP AS NON CORE | Summary: Telomere trimming generating t-circles involves XRCC3 in cancer cells and stimulated lymphocytes. Reason: Supported; non-core. Supporting Evidence: PMID:21903669 the mechanism involves the XRCC3 homologous recombination (HR) protein and generates single-stranded C-rich telomeric DNA |
| GO:0090657 telomeric loop disassembly | TAS PMID:27918544 A balance between elongation and trimming regulates telomere... | KEEP AS NON CORE | Summary: XRCC3 implicated in t-loop resolution producing C-rich overhangs in hESCs. Reason: Supported by the cited study; non-core telomeric HR role. Supporting Evidence: PMID:27918544 We demonstrate that XRCC3 and Nbs1 mediate telomere attrition by catalyzing the formation of T-circles and C-rich overhangs |
| GO:0090737 telomere maintenance via telomere trimming | IGI PMID:27918544 A balance between elongation and trimming regulates telomere... | KEEP AS NON CORE | Summary: XRCC3 and NBS1 mediate telomere trimming (T-circles, C-rich overhangs) in hESCs. Reason: Supported; non-core. Supporting Evidence: PMID:27918544 We demonstrate that XRCC3 and Nbs1 mediate telomere attrition by catalyzing the formation of T-circles and C-rich overhangs |
| GO:0140664 ATP-dependent DNA damage sensor activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: ATP-dependent DNA damage sensor activity mapped from the RecA ATP-binding InterPro domain. Reason: The InterPro2GO mapping transfers a RecA/RAD51-family sensor/recombinase activity to all members. XRCC3 is not a damage sensor; it acts within CX3/X3CDX2 as a RAD51 filament regulator (5' cap, strand-exchange stimulation). Consistent with the RAD51C and XRCC2 reviews. Supporting Evidence: PMID:42682019 the X3CDX2 complex also caps the RAD51 nucleofilament at the 5β² end, with XRCC3 directly interacting with RAD51 and XRCC2 forming the cap |
| GO:0140619 DNA strand exchange activator activity | IDA PMID:42020761 Structural insight into how RAD51 paralog exchange regulates... | NEW | Summary: Proposed new annotation. XRCC3-containing paralog complexes (CX3, RAD51-X3C, X3CDX2/DX2-CX3) bind RAD51 and stimulate RAD51-mediated DNA strand exchange / D-loop formation, shown independently by three groups with purified human proteins. Reason: This is the best available molecular-function description of how XRCC3 acts: GO:0140619 is defined as binding to and increasing a DNA strand exchange activity, and the comparator RAD51AP1 carries it for the equivalent RAD51-stimulating role. XRCC3 itself does work in the step: its unique loop insertion contacts RAD51, and a RAD51-interaction-defective XRCC3 mutant fails to overcome RPA inhibition of strand exchange. contributes_to because activity is measured on paralog complexes, not XRCC3 alone. The structures are recent (2026), so absence from GOA reflects publication timing rather than a curatorial decision. Supporting Evidence: PMID:42020761 RAD51βX3C displayed significantly enhanced DNA strand exchange activity over RAD51 alone across the protein concentrations tested PMID:42020761 the RAD51-interaction-defective XRCC3 loopΞ/quad mutant failed to support synergistic ssDNA binding with RAD51 or the ability to overcome RPA-mediated inhibition of strand exchange PMID:41196948 The XRCC3 complex, and to a lesser extent the CX3 complex, stimulated RAD51-mediated strand invasion PMID:41772053 When RPA was added before RAD51, BCDX2-CX3 and CX3 strongly stimulated D-loop formation |
| GO:0062176 R-loop processing | IMP PMID:41719405 RAD51C-XRCC3 complex regulates FANCM-mediated R-loop resolut... | NEW | Summary: Proposed new annotation. The CX3 complex suppresses R-loops and transcription-replication collisions by binding FANCM and recruiting it to R-loop sites; XRCC3 is enriched at R-loop-prone loci and co-immunoprecipitates FANCM. Reason: XRCC3 contributes structure the step depends on (an adaptor that recruits the FANCM translocase), which meets the participation test; GO:0062176 is also carried by non-catalytic regulators/recruiters in human (QuickGO exact query in taxon 9606 gives SIRT7 IDA PMID:28790157, SRPK2 IDA PMID:28076779, NFAT5 IDA PMID:34049076), so this is not against an existing convention. The function is separable from fork maintenance and from XRCC3 S225 phosphorylation. Evidence is from a single recent study (2026), so flagged as non-core pending replication. Supporting Evidence: PMID:41719405 the CX3 complex physically interacts with FANCM and facilitates its recruitment to the R-loop sites to promote its resolution PMID:41719405 CX3 complex suppresses R-loops, transcription-replication collisions (TRCs), and associated genome instability PMID:41719405 chromatin immunoprecipitation (ChIP) assay also showed enrichment of RAD51C and XRCC3, but not XRCC2, at the R-loop prone loci APOE and RPL13A in the genome |
| GO:0042645 mitochondrial nucleoid | IDA PMID:29158291 RAD51C/XRCC3 Facilitates Mitochondrial DNA Replication and M... | NEW | Summary: Proposed new annotation. RAD51C/XRCC3 co-fractionates with mitochondrial nucleoids, is salt-resistant in nucleoid fractions, and is lost on mtDNA depletion. Reason: Refines the existing GO:0005739 mitochondrion annotation with direct experimental evidence for nucleoid association; location only (no process claim) and therefore low risk. Supporting Evidence: PMID:29158291 RAD51C/XRCC3 is an additional component of the mitochondrial nucleoid having nucleus-independent roles in mtDNA maintenance PMID:29158291 indicating that RAD51, RAD51C, and XRCC3 are integral parts of the mitochondrial nucleoid |
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Download this section (compressed HTML)Q: Which XRCC3-containing assembly (CX3, RAD51-X3C octamer, X3CDX2, or BCDX2-CX3) executes each cellular role - HR, stalled-fork restart, collapsed-fork recovery, R-loop suppression - and does GO need a complex term for X3CDX2 (RAD51C-RAD51D-XRCC2-XRCC3), which currently has none?
Q: Is the reported XRCC3 role in Holliday junction resolution (with GEN1) a direct activity of CX3 on junctions, or a downstream consequence of its 5' capping/stabilization of RAD51 filaments and D-loops?
Q: Does XRCC3 ATP hydrolysis (required for fork restart and RAD51 disengagement) contribute to strand-exchange stimulation, given that X3CDX2 shows minimal ATPase activity?
Experiment: Separation-of-function XRCC3 mutants that disrupt the RAD51-contacting loop insertion versus the RAD51C or DX2 interfaces, tested in cells for HR (DR-GFP), stalled versus collapsed fork restart, and R-loop suppression.
Hypothesis: Distinct XRCC3 interfaces specify distinct paralog assemblies and thus separable cellular functions.
Experiment: Reconstitution of D-loop / Holliday junction processing with purified CX3 or X3CDX2 plus GEN1 to test whether XRCC3-containing complexes directly promote branch migration or junction cleavage.
Hypothesis: XRCC3 affects junction resolution indirectly via D-loop stabilization rather than direct stimulation of GEN1.
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