XRCC2 (DNA repair protein XRCC2; also FANCU) is one of five human RAD51 paralogs and a RecA/RAD51-family P-loop NTPase. It is an obligate structural subunit of the BCDX2 complex (RAD51B-RAD51C-RAD51D-XRCC2), one of the two RAD51-paralog assemblies (the other being CX3, RAD51C-XRCC3). BCDX2 functions as a homologous-recombination mediator: it binds single-stranded DNA and branched DNA structures (four-way/Holliday junctions and replication forks) and stimulates the nucleation and extension of the RAD51 nucleoprotein filament on RPA-coated ssDNA, an activity essential for homologous recombination. Within the complex, RAD51C-RAD51D-XRCC2 structurally mimic three aligned RAD51 protomers; XRCC2 binds ATP through canonical Walker A/B motifs, but the ATP hydrolysis that drives the high-affinity ssDNA-binding, filament-promoting state is contributed by RAD51B and RAD51C. BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment, and also participates in replication fork remodeling/protection and interstrand crosslink repair. XRCC2 localizes predominantly to the nucleus/nucleoplasm and is also found at centrosomes. Biallelic loss-of-function causes Fanconi anemia complementation group U, and XRCC2 deficiency produces hypersensitivity to DNA cross-linking agents, chromosome instability and defective homologous recombination; hypomorphic variants underlie meiotic phenotypes (spermatogenic failure, premature ovarian failure) and contribute to cancer predisposition.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000400 four-way junction DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: As part of the BCDX2 complex, XRCC2 contributes to specific binding of four-way (Holliday) junction DNA. Experimentally supported and phylogenetically consistent. Reason: The purified BCDX2 complex binds with high specificity to branched DNA including Holliday (four-way) junctions; XRCC2 is an obligate subunit contributing to this DNA-binding activity. The contributes_to qualifier is appropriate for a complex subunit. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally |
| GO:0000724 double-strand break repair via homologous recombination | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. XRCC2, via BCDX2, promotes RAD51 filament assembly required for double-strand break repair by homologous recombination. Reason: Well established for XRCC2 and the RAD51 paralogs; XRCC2-deficient cells are defective in HR and RAD51 focus formation. This is the central function of the gene. Supporting Evidence: PMID:37344587 BCDX2 stimulates the nucleation and extension of RAD51 |
| GO:0005657 replication fork | IBA GO_REF:0000033 | ACCEPT | Summary: XRCC2/BCDX2 acts at replication forks, binding fork structures and functioning in fork remodeling, protection and restart. Reason: The BCDX2 complex binds replication-fork DNA with high specificity and restrains fork progression/promotes fork reversal under replication stress. Supporting Evidence: PMID:32669601 the BCDX2 subcomplex restrains fork progression upon stress, promoting fork |
| GO:0005813 centrosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: XRCC2 co-localizes with centrosomes; this is a secondary localization associated with a role in mitotic stability rather than the core HR-mediator function. Reason: Centrosome association is experimentally observed but represents a peripheral/secondary activity (mitotic stability) likely downstream of the primary HR role; not a core molecular function of XRCC2. Supporting Evidence: PMID:21276791 XRCC2 and other HR proteins, including the key |
| GO:0033063 Rad51B-Rad51C-Rad51D-XRCC2 complex | IBA GO_REF:0000033 | ACCEPT | Summary: XRCC2 is an obligate subunit of the BCDX2 complex. This is the defining structural annotation for the protein. Reason: Biochemically purified and structurally resolved; XRCC2 is one of the four subunits of BCDX2. Supporting Evidence: PMID:11751635 the five paralogs exist in two distinct complexes in human cells: one contains RAD51B, RAD51C, RAD51D, and XRCC2 (defined as BCDX2) |
| GO:0042148 DNA strand invasion | IBA GO_REF:0000033 | ACCEPT | Summary: XRCC2, via its subcomplex/BCDX2 mediator activity, promotes homologous pairing and strand invasion during HR. Reason: The purified Xrcc2*Rad51D subcomplex catalyzes homologous pairing between ssDNA and dsDNA, and BCDX2 promotes RAD51 filament assembly that carries out strand invasion. Supporting Evidence: PMID:11834724 pairing between single-stranded and double-stranded DNA |
| GO:0000724 double-strand break repair via homologous recombination | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation to the core HR process; consistent with experimental and phylogenetic evidence. Reason: Redundant with, and consistent with, the experimentally and IBA-supported HR annotation. Supporting Evidence: PMID:10517641 XRCC2 is essential for the efficient repair of DNA double-strand breaks by homologous recombination between sister chromatids |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: XRCC2, within BCDX2, binds ssDNA and branched DNA. DNA binding is a broad but correct parent term. Reason: Correct though general; more specific supported terms (four-way junction DNA binding) are also annotated. Acceptable as a broad electronic annotation. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: XRCC2 binds ATP via canonical Walker A (K54/T55) and Walker B (D149) motifs, as resolved in the BCDX2 cryo-EM structure. Reason: Directly confirmed structurally; XRCC2 binds ATP even though the catalytic ATPase driving BCDX2's filament-promoting activity is contributed by RAD51B and RAD51C. Supporting Evidence: PMID:37344587 XRCC2 binds ATP in a near-identical arrangement via Walker A K54/T55 and Walker B D149 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: XRCC2 is a nuclear protein, consistent with its DNA-repair function. Reason: Nuclear localization is experimentally documented (UniProt SUBCELLULAR LOCATION; PMID:21276791). Supporting Evidence: PMID:21276791 XRCC2 and other HR proteins, including the key |
| GO:0005657 replication fork | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic annotation to replication fork, consistent with experimental data. Reason: Redundant with experimentally supported replication-fork annotations. |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Centrosome localization from UniProt subcellular-location mapping; a secondary localization. Reason: Consistent with experimental IDA (PMID:21276791) but peripheral to the core HR-mediator function. |
| GO:0006281 DNA repair | IEA GO_REF:0000002 | ACCEPT | Summary: Broad DNA-repair annotation; correct parent of the specific HR role. Reason: Correct though general; the more specific HR term is also annotated. |
| GO:0033063 Rad51B-Rad51C-Rad51D-XRCC2 complex | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic annotation of BCDX2 membership; consistent with experimental evidence. Reason: Redundant with the experimentally supported BCDX2 complex annotations. |
| GO:0140664 ATP-dependent DNA damage sensor activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro-based electronic mapping propagated from the RecA/RAD51 ATP-binding domain. XRCC2 is a RAD51-filament-assembly mediator, not a demonstrated ATP-dependent DNA damage sensor; the ATP hydrolysis that drives BCDX2 is contributed by RAD51B and RAD51C. Reason: This is an over-propagation of a RecA/RAD51-family ATPase/damage-sensor function onto XRCC2. Structural analysis shows XRCC2 binds but is not established to hydrolyze ATP as a damage sensor; its molecular role is as a mediator subunit promoting RAD51 filament nucleation/extension. The term overstates an independent catalytic sensor activity. Supporting Evidence: PMID:37344587 BCDX2 promotes RAD51 filament nucleation and growth in an ATP hydrolysis dependent manner PMID:11301337 it does not make use of ATP binding to promote this function |
| GO:0005515 protein binding | IPI PMID:10749867 Evidence for simultaneous protein interactions between human... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding IPI (RAD51D partner). Uninformative as a molecular function; the biologically meaningful interaction is captured by the BCDX2 complex annotation. Reason: 'protein binding' (GO:0005515) is uninformative per curation guidelines. The underlying RAD51D/paralog interaction is better represented by GO:0033063 (BCDX2 complex). |
| GO:0005515 protein binding | IPI PMID:10871607 The RAD51 family member, RAD51L3, is a DNA-stimulated ATPase... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding IPI (RAD51D/RAD51L3 partner); uninformative as MF. Reason: Uninformative 'protein binding' term; the meaningful RAD51D interaction is captured by the BCDX2 complex annotation. |
| GO:0005515 protein binding | IPI PMID:11751635 Identification and purification of two distinct complexes co... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding IPI within the RAD51-paralog complexes study. Reason: Uninformative 'protein binding'; the same paper supports the specific BCDX2 complex annotation (GO:0033063), which should carry the information. |
| GO:0005515 protein binding | IPI PMID:11842113 Involvement of Rad51C in two distinct protein complexes of R... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding IPI (RAD51C/RAD51D partners in paralog complexes). Reason: Uninformative 'protein binding'; captured better by the BCDX2 complex annotation. |
| GO:0005515 protein binding | IPI PMID:12975363 Functional interaction between the Bloom's syndrome helicase... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding IPI (RAD51D/BLM interaction context). Reason: Uninformative 'protein binding' term for a specific partner interaction. |
| GO:0005515 protein binding | IPI PMID:16710300 Sws1 is a conserved regulator of homologous recombination in... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding IPI (SWS1/HR regulator context). Reason: Uninformative 'protein binding' term. |
| GO:0005515 protein binding | IPI PMID:24141787 Breast cancer-associated missense mutants of the PALB2 WD40 ... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding IPI (PALB2/RAD51C interactome context). Reason: Uninformative 'protein binding' term. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding IPI (proteome-scale map). Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding IPI. Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding IPI. Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005515 protein binding | IPI PMID:28864920 Discovery of mutations in homologous recombination genes in ... | MARK AS OVER ANNOTATED | Summary: Protein-binding IPI (HR-gene mutation/interaction study). Reason: Uninformative 'protein binding' term. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding IPI (variant interaction landscape). Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput binary interactome protein-binding IPI. Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding IPI (RAD51C/RAD51D partners). Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005515 protein binding | IPI PMID:34591612 A protein interaction landscape of breast cancer. | MARK AS OVER ANNOTATED | Summary: Protein-binding IPI (breast-cancer interactome landscape). Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding IPI (multimodal cell maps). Reason: Uninformative 'protein binding' from a large-scale interactome screen. |
| GO:0005657 replication fork | NAS PMID:32669601 Sequential role of RAD51 paralog complexes in replication fo... | ACCEPT | Summary: XRCC2/BCDX2 localizes to and acts at replication forks in fork remodeling and restart. Reason: Single-molecule and cellular data place the BCDX2 subcomplex at stressed replication forks, where it restrains fork progression and promotes fork reversal. Supporting Evidence: PMID:32669601 the BCDX2 subcomplex restrains fork progression upon stress, promoting fork PMID:30566856 restrain active DNA synthesis during |
| GO:0033063 Rad51B-Rad51C-Rad51D-XRCC2 complex | IPI PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: Experimentally purified BCDX2 complex membership. Defining structural annotation for XRCC2. Reason: The four-subunit BCDX2 complex was purified to homogeneity and its composition established biochemically. Supporting Evidence: PMID:11751635 one contains RAD51B, RAD51C, RAD51D, and XRCC2 (defined as BCDX2) |
| GO:0097435 supramolecular fiber organization | IDA PMID:37344587 Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tum... | MODIFY | Summary: Captures BCDX2's mediator activity: promoting the nucleation and extension of RAD51 nucleoprotein filaments (supramolecular fibers) on ssDNA. Reason: The 2023 structure/function study directly demonstrates that BCDX2 increases both the quantity (nucleation) and length (extension) of RAD51 filaments in an ATP-hydrolysis- dependent manner. That is XRCC2's core contribution, but supramolecular fiber organization is a generic parent that says nothing about recombinases. 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 we found that BCDX2 increases both the quantity (nucleation) and length (growth) of RAD51 filaments |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685318 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway (BCDX2 complex formation). Reason: Consistent with the nuclear localization of XRCC2 acting in HR; nucleoplasm is a valid refinement of nucleus. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685341 | ACCEPT | Summary: Nucleoplasmic localization from Reactome (BCDX2 stabilizes RAD51 filament). Reason: Consistent with XRCC2's nuclear HR-mediator function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5685838 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686410 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686440 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686469 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5686483 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693539 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693584 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693589 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693593 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5693620 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway. Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9701199 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway (defective-BRCA1 context). Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704330 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway (defective-PALB2 context). Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9704408 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway (defective-PALB2 context). Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9709601 | ACCEPT | Summary: Nucleoplasmic localization from Reactome HR pathway (defective-BRCA2 context). Reason: Consistent with XRCC2's nuclear localization. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9853389 | ACCEPT | Summary: Nucleoplasmic localization from Reactome (FIGNL1 binds RAD51 context). Reason: Consistent with XRCC2's nuclear localization. |
| GO:0000278 mitotic cell cycle | IMP PMID:21276791 Homologous recombination proteins are associated with centro... | KEEP AS NON CORE | Summary: XRCC2-deficient cells show mitotic instability/catastrophe linked to centrosome disruption. A broad, secondary process term. Reason: Experimentally supported but very general and peripheral to the core HR-mediator role; likely an indirect consequence of genome instability rather than a distinct XRCC2 function. Supporting Evidence: PMID:21276791 centrosome disruption is dynamic |
| 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 binds Holliday (four-way) junctions with high specificity; XRCC2 contributes to this activity as a complex subunit. Reason: Experimentally supported specific DNA-binding molecular function; contributes_to is the correct qualifier for a subunit of the DNA-binding complex. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally |
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:23149936 Rad51 paralog complexes BCDX2 and CX3 act at different stage... | ACCEPT | Summary: Loss of BCDX2 function impairs HR; the complex acts downstream of BRCA2 and upstream of RAD51 recruitment. Reason: Directly demonstrated genetic requirement for XRCC2/BCDX2 in the BRCA1-BRCA2-dependent HR pathway. Core function. Supporting Evidence: 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 binds replication-fork DNA structures with high specificity (direct EM). Reason: Direct experimental visualization of BCDX2 binding forked DNA; supports replication-fork localization. Supporting Evidence: PMID:20207730 both complexes bind with exceptionally |
| GO:0005813 centrosome | IDA PMID:21276791 Homologous recombination proteins are associated with centro... | KEEP AS NON CORE | Summary: XRCC2 co-localizes with centrosomes throughout the cell cycle (direct observation); a secondary localization. Reason: Experimentally supported but peripheral to the core HR-mediator function; retained as a non-core localization. Supporting Evidence: PMID:21276791 XRCC2 and other HR proteins, including the key |
| GO:0007098 centrosome cycle | IMP PMID:21276791 Homologous recombination proteins are associated with centro... | KEEP AS NON CORE | Summary: XRCC2 deficiency disrupts centrosome integrity, linking XRCC2 to centrosome/mitotic stability. A secondary process. Reason: Experimentally supported but a peripheral role likely secondary to genome-instability effects; not a core molecular function. Supporting Evidence: PMID:21276791 centrosome disruption is dynamic |
| GO:0033063 Rad51B-Rad51C-Rad51D-XRCC2 complex | IDA PMID:11751635 Identification and purification of two distinct complexes co... | ACCEPT | Summary: Direct biochemical demonstration of BCDX2 complex membership. Reason: BCDX2 was purified to homogeneity with XRCC2 as a subunit. Supporting Evidence: PMID:11751635 one contains RAD51B, RAD51C, RAD51D, and XRCC2 (defined as BCDX2) |
| GO:0042148 DNA strand invasion | IDA PMID:11834724 Homologous pairing and ring and filament structure formation... | ACCEPT | Summary: The purified Xrcc2*Rad51D subcomplex catalyzes homologous pairing between ssDNA and dsDNA, the strand-invasion reaction of HR. Reason: Direct in vitro demonstration of homologous-pairing (strand-invasion) activity by an XRCC2-containing subcomplex. Supporting Evidence: PMID:11834724 pairing between single-stranded and double-stranded DNA |
| GO:0006281 DNA repair | IGI PMID:10422536 The XRCC2 and XRCC3 repair genes are required for chromosome... | ACCEPT | Summary: XRCC2 (and XRCC3) are required for chromosome stability; XRCC2-mutant cells accumulate breaks, deletions and translocations. Broad DNA-repair role. Reason: Genetic-interaction evidence that XRCC2 maintains chromosome stability via DNA repair; correct though general parent of the specific HR term. Supporting Evidence: PMID:10422536 play essential roles in |
| GO:0006281 DNA repair | TAS PMID:9628903 The XRCC2 DNA repair gene from human and mouse encodes a nov... | ACCEPT | Summary: XRCC2 identified as a recA/RAD51-family DNA-repair gene that complements cross-linker hypersensitivity of irs1 cells. Reason: Author-stated DNA-repair role, consistent with all downstream evidence. Supporting Evidence: PMID:9628903 elevated in mouse testis, suggesting an additional role |
| GO:0051321 meiotic cell cycle | TAS PMID:9628903 The XRCC2 DNA repair gene from human and mouse encodes a nov... | KEEP AS NON CORE | Summary: XRCC2 has a meiotic role: its transcript is elevated in testis and biallelic hypomorphic variants cause meiotic arrest/infertility (SPGF50, POF17). Reason: Meiotic involvement is genuine (supported by expression and human infertility phenotypes) but represents a tissue/context-specific deployment of the same HR machinery rather than a distinct core molecular function. Supporting Evidence: PMID:9628903 elevated in mouse testis, suggesting an additional role PMID:30042186 XRCC2 recessive mutation causing meiotic arrest and infertility in humans |
| GO:0036297 interstrand cross-link repair | IMP PMID:27208205 Complementation of hypersensitivity to DNA interstrand cross... | NEW | Summary: XRCC2 (FANCU) is required for repair of DNA interstrand crosslinks: wild-type XRCC2 corrects the mitomycin-C hypersensitivity, chromosome breakage and G2-M accumulation of Fanconi anemia patient cells carrying biallelic XRCC2 mutation, placing XRCC2 in the FA-BRCA ICL-repair pathway (acting late, downstream of FANCD2 monoubiquitination). Reason: Not present in GOA but well-evidenced and a genuine gap: XRCC2 is Fanconi anemia complementation group U (FANCU). Interstrand cross-link repair (GO:0036297) is a specific, correctly-branched DNA-repair biological process distinct from the general DNA repair (GO:0006281) and DSBR-HR (GO:0000724) terms already annotated. Genetic complementation of ICL-specific cellular phenotypes directly demonstrates the role. Supporting Evidence: PMID:27208205 all related to the repair of DNA interstrand crosslinks, including |
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Download this section (compressed HTML)Q: Does XRCC2's own ATP binding (Walker A K54/T55, Walker B D149) contribute catalytically to BCDX2 function, or is it purely structural, given that RAD51B and RAD51C provide the coupled ATPase activity that drives RAD51 filament assembly?
Q: Is the centrosome/mitotic-stability phenotype of XRCC2-deficient cells a direct function of XRCC2 at the centrosome, or an indirect consequence of unrepaired DNA damage and genome instability?
Experiment: Separation-of-function XRCC2 Walker-motif mutants (ATP-binding-deficient) reconstituted into BCDX2 to test whether XRCC2 nucleotide binding is required for RAD51 filament nucleation and extension versus complex assembly.
Hypothesis: XRCC2 ATP binding is structural and largely dispensable for the catalytic drive of RAD51 filament assembly, which is provided by RAD51B and RAD51C.
Experiment: Single-molecule assays of RAD51 filament assembly with BCDX2 reconstituted from cancer- and Fanconi-associated XRCC2 variants to map variant effects onto the mediator activity.
Hypothesis: Pathogenic XRCC2 variants impair BCDX2's ability to nucleate and extend RAD51 filaments.
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