id: O43543
gene_symbol: XRCC2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
- term:
    id: GO:0000400
    label: four-way junction DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: >-
      As part of the BCDX2 complex, XRCC2 contributes to specific binding of four-way
      (Holliday) junction DNA. Experimentally supported and phylogenetically consistent.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20207730
      supporting_text: both complexes bind with exceptionally
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. XRCC2, via BCDX2, promotes RAD51 filament assembly required
      for double-strand break repair by homologous recombination.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:37344587
      supporting_text: BCDX2 stimulates the nucleation and extension of RAD51
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      XRCC2/BCDX2 acts at replication forks, binding fork structures and functioning in fork
      remodeling, protection and restart.
    action: ACCEPT
    reason: >-
      The BCDX2 complex binds replication-fork DNA with high specificity and restrains fork
      progression/promotes fork reversal under replication stress.
    supported_by:
    - reference_id: PMID:32669601
      supporting_text: the BCDX2 subcomplex restrains fork progression upon stress, promoting fork
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:21276791
      supporting_text: XRCC2 and other HR proteins, including the key
- term:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      XRCC2 is an obligate subunit of the BCDX2 complex. This is the defining structural
      annotation for the protein.
    action: ACCEPT
    reason: >-
      Biochemically purified and structurally resolved; XRCC2 is one of the four subunits of
      BCDX2.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: 'the five paralogs exist in two distinct complexes in human cells: one contains RAD51B, RAD51C, RAD51D, and XRCC2 (defined as BCDX2)'
- term:
    id: GO:0042148
    label: DNA strand invasion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      XRCC2, via its subcomplex/BCDX2 mediator activity, promotes homologous pairing and
      strand invasion during HR.
    action: ACCEPT
    reason: >-
      The purified Xrcc2*Rad51D subcomplex catalyzes homologous pairing between ssDNA and
      dsDNA, and BCDX2 promotes RAD51 filament assembly that carries out strand invasion.
    supported_by:
    - reference_id: PMID:11834724
      supporting_text: pairing between single-stranded and double-stranded DNA
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro-based electronic annotation to the core HR process; consistent with
      experimental and phylogenetic evidence.
    action: ACCEPT
    reason: Redundant with, and consistent with, the experimentally and IBA-supported HR annotation.
    supported_by:
    - reference_id: PMID:10517641
      supporting_text: XRCC2 is essential for the efficient repair of DNA double-strand breaks by homologous recombination between sister chromatids
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      XRCC2, within BCDX2, binds ssDNA and branched DNA. DNA binding is a broad but correct
      parent term.
    action: ACCEPT
    reason: >-
      Correct though general; more specific supported terms (four-way junction DNA binding)
      are also annotated. Acceptable as a broad electronic annotation.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      XRCC2 binds ATP via canonical Walker A (K54/T55) and Walker B (D149) motifs, as resolved
      in the BCDX2 cryo-EM structure.
    action: ACCEPT
    reason: >-
      Directly confirmed structurally; XRCC2 binds ATP even though the catalytic ATPase driving
      BCDX2's filament-promoting activity is contributed by RAD51B and RAD51C.
    supported_by:
    - reference_id: PMID:37344587
      supporting_text: XRCC2 binds ATP in a near-identical arrangement via Walker A K54/T55 and Walker B D149
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: XRCC2 is a nuclear protein, consistent with its DNA-repair function.
    action: ACCEPT
    reason: Nuclear localization is experimentally documented (UniProt SUBCELLULAR LOCATION; PMID:21276791).
    supported_by:
    - reference_id: PMID:21276791
      supporting_text: XRCC2 and other HR proteins, including the key
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Electronic annotation to replication fork, consistent with experimental data.
    action: ACCEPT
    reason: Redundant with experimentally supported replication-fork annotations.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Centrosome localization from UniProt subcellular-location mapping; a secondary localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with experimental IDA (PMID:21276791) but peripheral to the core HR-mediator
      function.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Broad DNA-repair annotation; correct parent of the specific HR role.
    action: ACCEPT
    reason: Correct though general; the more specific HR term is also annotated.
- term:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: Electronic annotation of BCDX2 membership; consistent with experimental evidence.
    action: ACCEPT
    reason: Redundant with the experimentally supported BCDX2 complex annotations.
- term:
    id: GO:0140664
    label: ATP-dependent DNA damage sensor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:37344587
      supporting_text: BCDX2 promotes RAD51 filament nucleation and growth in an ATP hydrolysis dependent manner
    - reference_id: PMID:11301337
      supporting_text: it does not make use of ATP binding to promote this function
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10749867
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding IPI (RAD51D partner). Uninformative as a molecular function; the
      biologically meaningful interaction is captured by the BCDX2 complex annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' (GO:0005515) is uninformative per curation guidelines. The underlying
      RAD51D/paralog interaction is better represented by GO:0033063 (BCDX2 complex).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10871607
  qualifier: enables
  review:
    summary: Generic protein-binding IPI (RAD51D/RAD51L3 partner); uninformative as MF.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative 'protein binding' term; the meaningful RAD51D interaction is captured by the
      BCDX2 complex annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11751635
  qualifier: enables
  review:
    summary: Generic protein-binding IPI within the RAD51-paralog complexes study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative 'protein binding'; the same paper supports the specific BCDX2 complex
      annotation (GO:0033063), which should carry the information.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11842113
  qualifier: enables
  review:
    summary: Generic protein-binding IPI (RAD51C/RAD51D partners in paralog complexes).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding'; captured better by the BCDX2 complex annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12975363
  qualifier: enables
  review:
    summary: Generic protein-binding IPI (RAD51D/BLM interaction context).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' term for a specific partner interaction.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16710300
  qualifier: enables
  review:
    summary: Generic protein-binding IPI (SWS1/HR regulator context).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24141787
  qualifier: enables
  review:
    summary: Generic protein-binding IPI (PALB2/RAD51C interactome context).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding IPI (proteome-scale map).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding IPI.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding IPI.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28864920
  qualifier: enables
  review:
    summary: Protein-binding IPI (HR-gene mutation/interaction study).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding IPI (variant interaction landscape).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome protein-binding IPI.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding IPI (RAD51C/RAD51D partners).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591612
  qualifier: enables
  review:
    summary: Protein-binding IPI (breast-cancer interactome landscape).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: High-throughput interactome protein-binding IPI (multimodal cell maps).
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a large-scale interactome screen.
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: NAS
  original_reference_id: PMID:32669601
  qualifier: located_in
  review:
    summary: >-
      XRCC2/BCDX2 localizes to and acts at replication forks in fork remodeling and restart.
    action: ACCEPT
    reason: >-
      Single-molecule and cellular data place the BCDX2 subcomplex at stressed replication
      forks, where it restrains fork progression and promotes fork reversal.
    supported_by:
    - reference_id: PMID:32669601
      supporting_text: the BCDX2 subcomplex restrains fork progression upon stress, promoting fork
    - reference_id: PMID:30566856
      supporting_text: restrain active DNA synthesis during
- term:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
  evidence_type: IPI
  original_reference_id: PMID:11751635
  qualifier: part_of
  review:
    summary: >-
      Experimentally purified BCDX2 complex membership. Defining structural annotation for XRCC2.
    action: ACCEPT
    reason: >-
      The four-subunit BCDX2 complex was purified to homogeneity and its composition
      established biochemically.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: 'one contains RAD51B, RAD51C, RAD51D, and XRCC2 (defined as BCDX2)'
- term:
    id: GO:0097435
    label: supramolecular fiber organization
  evidence_type: IDA
  original_reference_id: PMID:37344587
  qualifier: involved_in
  review:
    summary: >-
      Captures BCDX2's mediator activity: promoting the nucleation and extension of RAD51
      nucleoprotein filaments (supramolecular fibers) on ssDNA.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0000730
      label: DNA recombinase assembly
    supported_by:
    - reference_id: PMID:37344587
      supporting_text: we found that BCDX2 increases both the quantity (nucleation) and length (growth) of RAD51 filaments
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685318
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway (BCDX2 complex formation).
    action: ACCEPT
    reason: Consistent with the nuclear localization of XRCC2 acting in HR; nucleoplasm is a valid refinement of nucleus.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685341
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome (BCDX2 stabilizes RAD51 filament).
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear HR-mediator function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685838
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686410
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686440
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686469
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686483
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693539
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693584
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693589
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693593
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693620
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway.
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9701199
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway (defective-BRCA1 context).
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9704330
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway (defective-PALB2 context).
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9704408
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway (defective-PALB2 context).
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709601
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome HR pathway (defective-BRCA2 context).
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9853389
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization from Reactome (FIGNL1 binds RAD51 context).
    action: ACCEPT
    reason: Consistent with XRCC2's nuclear localization.
- term:
    id: GO:0000278
    label: mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:21276791
  qualifier: involved_in
  review:
    summary: >-
      XRCC2-deficient cells show mitotic instability/catastrophe linked to centrosome
      disruption. A broad, secondary process term.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:21276791
      supporting_text: centrosome disruption is dynamic
- term:
    id: GO:0000400
    label: four-way junction DNA binding
  evidence_type: IDA
  original_reference_id: PMID:20207730
  qualifier: contributes_to
  review:
    summary: >-
      Direct EM demonstration that BCDX2 binds Holliday (four-way) junctions with high
      specificity; XRCC2 contributes to this activity as a complex subunit.
    action: ACCEPT
    reason: >-
      Experimentally supported specific DNA-binding molecular function; contributes_to is the
      correct qualifier for a subunit of the DNA-binding complex.
    supported_by:
    - reference_id: PMID:20207730
      supporting_text: both complexes bind with exceptionally
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IMP
  original_reference_id: PMID:23149936
  qualifier: involved_in
  review:
    summary: >-
      Loss of BCDX2 function impairs HR; the complex acts downstream of BRCA2 and upstream of
      RAD51 recruitment.
    action: ACCEPT
    reason: >-
      Directly demonstrated genetic requirement for XRCC2/BCDX2 in the BRCA1-BRCA2-dependent HR
      pathway. Core function.
    supported_by:
    - reference_id: PMID:23149936
      supporting_text: the BCDX2 complex acts downstream of BRCA2 recruitment but
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: IDA
  original_reference_id: PMID:20207730
  qualifier: located_in
  review:
    summary: BCDX2 binds replication-fork DNA structures with high specificity (direct EM).
    action: ACCEPT
    reason: >-
      Direct experimental visualization of BCDX2 binding forked DNA; supports replication-fork
      localization.
    supported_by:
    - reference_id: PMID:20207730
      supporting_text: both complexes bind with exceptionally
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:21276791
  qualifier: located_in
  review:
    summary: >-
      XRCC2 co-localizes with centrosomes throughout the cell cycle (direct observation);
      a secondary localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported but peripheral to the core HR-mediator function; retained as a
      non-core localization.
    supported_by:
    - reference_id: PMID:21276791
      supporting_text: XRCC2 and other HR proteins, including the key
- term:
    id: GO:0007098
    label: centrosome cycle
  evidence_type: IMP
  original_reference_id: PMID:21276791
  qualifier: involved_in
  review:
    summary: >-
      XRCC2 deficiency disrupts centrosome integrity, linking XRCC2 to centrosome/mitotic
      stability. A secondary process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported but a peripheral role likely secondary to genome-instability
      effects; not a core molecular function.
    supported_by:
    - reference_id: PMID:21276791
      supporting_text: centrosome disruption is dynamic
- term:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
  evidence_type: IDA
  original_reference_id: PMID:11751635
  qualifier: part_of
  review:
    summary: Direct biochemical demonstration of BCDX2 complex membership.
    action: ACCEPT
    reason: BCDX2 was purified to homogeneity with XRCC2 as a subunit.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: 'one contains RAD51B, RAD51C, RAD51D, and XRCC2 (defined as BCDX2)'
- term:
    id: GO:0042148
    label: DNA strand invasion
  evidence_type: IDA
  original_reference_id: PMID:11834724
  qualifier: involved_in
  review:
    summary: >-
      The purified Xrcc2*Rad51D subcomplex catalyzes homologous pairing between ssDNA and
      dsDNA, the strand-invasion reaction of HR.
    action: ACCEPT
    reason: >-
      Direct in vitro demonstration of homologous-pairing (strand-invasion) activity by an
      XRCC2-containing subcomplex.
    supported_by:
    - reference_id: PMID:11834724
      supporting_text: pairing between single-stranded and double-stranded DNA
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IGI
  original_reference_id: PMID:10422536
  qualifier: involved_in
  review:
    summary: >-
      XRCC2 (and XRCC3) are required for chromosome stability; XRCC2-mutant cells accumulate
      breaks, deletions and translocations. Broad DNA-repair role.
    action: ACCEPT
    reason: >-
      Genetic-interaction evidence that XRCC2 maintains chromosome stability via DNA repair;
      correct though general parent of the specific HR term.
    supported_by:
    - reference_id: PMID:10422536
      supporting_text: play essential roles in
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: TAS
  original_reference_id: PMID:9628903
  qualifier: involved_in
  review:
    summary: >-
      XRCC2 identified as a recA/RAD51-family DNA-repair gene that complements cross-linker
      hypersensitivity of irs1 cells.
    action: ACCEPT
    reason: Author-stated DNA-repair role, consistent with all downstream evidence.
    supported_by:
    - reference_id: PMID:9628903
      supporting_text: elevated in mouse testis, suggesting an additional role
- term:
    id: GO:0051321
    label: meiotic cell cycle
  evidence_type: TAS
  original_reference_id: PMID:9628903
  qualifier: involved_in
  review:
    summary: >-
      XRCC2 has a meiotic role: its transcript is elevated in testis and biallelic
      hypomorphic variants cause meiotic arrest/infertility (SPGF50, POF17).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:9628903
      supporting_text: elevated in mouse testis, suggesting an additional role
    - reference_id: PMID:30042186
      supporting_text: XRCC2 recessive mutation causing meiotic arrest and infertility in humans
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IMP
  original_reference_id: PMID:27208205
  qualifier: involved_in
  review:
    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).
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:27208205
      supporting_text: all related to the repair of DNA interstrand crosslinks, including
core_functions:
- description: >-
    As an obligate subunit of the BCDX2 complex (RAD51B-RAD51C-RAD51D-XRCC2), XRCC2 acts as a
    homologous-recombination mediator: BCDX2 binds ssDNA and branched DNA intermediates
    (four-way/Holliday junctions and replication forks) and stimulates the nucleation and
    extension of the RAD51 nucleoprotein filament on RPA-coated ssDNA, promoting homologous
    pairing and strand invasion during double-strand break and interstrand crosslink repair.
    XRCC2 binds ATP via canonical Walker A/B motifs and provides a structural protomer within
    the complex, while the ATP hydrolysis that powers filament assembly is contributed by
    RAD51B and RAD51C.
  supported_by:
  - reference_id: PMID:37344587
    supporting_text: BCDX2 stimulates the nucleation and extension of RAD51
  - reference_id: PMID:11834724
    supporting_text: pairing between single-stranded and double-stranded DNA
  contributes_to_molecular_function:
    id: GO:0000400
    label: four-way junction DNA binding
  directly_involved_in:
  - id: GO:0000724
    label: double-strand break repair via homologous recombination
  - id: GO:0042148
    label: DNA strand invasion
  - id: GO:0000730
    label: DNA recombinase assembly
  locations:
  - id: GO:0005657
    label: replication fork
  in_complex:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    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?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:10422536
  title: The XRCC2 and XRCC3 repair genes are required for chromosome stability in
    mammalian cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes XRCC2's requirement for chromosome stability; irs1
      (XRCC2-mutant) cells accumulate breaks/deletions/translocations. Supports the DNA repair
      IGI annotation.
- id: PMID:10517641
  title: Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous
    recombination.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Johnson, Liu, Jasin, Nature 1999). Classic demonstration that
      XRCC2-deficient hamster cells show >100-fold decrease in DSB-induced HR between sister
      chromatids while NHEJ is normal. Direct experimental support for the DSBR-HR annotation.
- id: PMID:10749867
  title: Evidence for simultaneous protein interactions between human Rad51 paralogs.
  findings: []
- id: PMID:10871607
  title: The RAD51 family member, RAD51L3, is a DNA-stimulated ATPase that forms a
    complex with XRCC2.
  findings: []
- id: PMID:11301337
  title: XRCC2 is a nuclear RAD51-like protein required for damage-dependent RAD51
    focus formation without the need for ATP binding.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (O'Regan et al., JBC 2001). XRCC2 localizes to the nucleus and is
      required for damage-dependent RAD51 focus formation, yet P-loop (ATP-binding) mutants
      still complement irs1. Supports the mediator (not ATP-dependent damage-sensor) role and
      the MARK_AS_OVER_ANNOTATED call on GO:0140664.
- id: PMID:11751635
  title: Identification and purification of two distinct complexes containing the
    five RAD51 paralogs.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text verified. Defines the BCDX2 complex (RAD51B-RAD51C-RAD51D-XRCC2) and shows it
      binds ssDNA and ssDNA gaps. Primary evidence for the GO:0033063 complex annotation.
- id: PMID:11834724
  title: Homologous pairing and ring and filament structure formation activities of
    the human Xrcc2*Rad51D complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract verified. Purified Xrcc2*Rad51D subcomplex catalyzes homologous pairing between
      ssDNA and dsDNA and forms ssDNA-dependent filaments. Supports DNA strand invasion.
- id: PMID:11842113
  title: Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs
    in human cells.
  findings: []
- id: PMID:12975363
  title: Functional interaction between the Bloom's syndrome helicase and the RAD51
    paralog, RAD51L3 (RAD51D).
  findings: []
- id: PMID:16710300
  title: Sws1 is a conserved regulator of homologous recombination in eukaryotic cells.
  findings: []
- id: PMID:20207730
  title: Ring-shaped Rad51 paralog protein complexes bind Holliday junctions and replication
    forks as visualized by electron microscopy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text verified. Direct EM shows BCDX2 binds Holliday junctions and replication forks
      with high specificity. Supports four-way junction DNA binding and replication-fork
      localization.
- id: PMID:21276791
  title: Homologous recombination proteins are associated with centrosomes and are
    required for mitotic stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract verified. Shows XRCC2 centrosome co-localization and mitotic-stability
      requirement; supports the (non-core) centrosome, centrosome cycle and mitotic cell cycle
      annotations.
- id: PMID:23149936
  title: Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent
    homologous recombination pathway.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. Places BCDX2 downstream of BRCA2 and upstream of RAD51 recruitment in HR;
      supports the DSBR-HR IMP annotation and the mediator model.
- id: PMID:24141787
  title: Breast cancer-associated missense mutants of the PALB2 WD40 domain, which
    directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
- id: PMID:27208205
  title: Complementation of hypersensitivity to DNA interstrand crosslinking agents
    demonstrates that XRCC2 is a Fanconi anaemia gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text verified (Park et al., J Med Genet 2016; PMC5035190). Establishes XRCC2 as
      Fanconi anemia complementation group U (FANCU): wild-type XRCC2 corrects MMC
      hypersensitivity, chromosome breakage and G2-M accumulation of patient cells with
      biallelic XRCC2 mutation; XRCC2 acts late in the FA-BRCA pathway (FANCD2
      monoubiquitination normal). Primary evidence for the new interstrand cross-link repair
      annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:28864920
  title: Discovery of mutations in homologous recombination genes in African-American
    women with breast cancer.
  findings: []
- id: PMID:30042186
  title: XRCC2 mutation causes meiotic arrest, azoospermia and infertility.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text verified (Yang et al., J Med Genet 2018; PMC6119352). Homozygous XRCC2
      p.Leu14Pro causes meiotic arrest, azoospermia and infertility in a consanguineous
      family; a knockin mouse reproduces meiotic arrest, azoospermia and premature ovarian
      failure. Direct human/mouse evidence strengthening the (non-core) meiotic cell cycle
      annotation beyond the original testis-expression inference.
- id: PMID:30566856
  title: XRCC2 Regulates Replication Fork Progression during dNTP Alterations.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified (Saxena, Somyajit, Nagaraju, Cell Rep 2018). XRCC2 (FANCU) and RAD51D
      restrain active DNA synthesis during dNTP alterations independently of HDR, via
      ATR-mediated phosphorylation of XRCC2 Ser247. XRCC2-specific corroboration of the
      replication-fork localization/function annotation.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32669601
  title: Sequential role of RAD51 paralog complexes in replication fork remodeling
    and restart.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. Shows the BCDX2 subcomplex restrains fork progression and promotes fork
      reversal under replication stress. Supports replication-fork localization/function.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34591612
  title: A protein interaction landscape of breast cancer.
  findings: []
- id: PMID:37344587
  title: Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tumour suppressor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text verified. Definitive cryo-EM structure/function of BCDX2: RAD51C-RAD51D-XRCC2
      mimic three aligned RAD51 protomers; BCDX2 stimulates RAD51 filament nucleation/extension
      in an ATP-hydrolysis-dependent manner (RAD51B/RAD51C ATPases); XRCC2 binds ATP via Walker
      A K54/T55, Walker B D149. Primary evidence for the mediator core function.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9628903
  title: The XRCC2 DNA repair gene from human and mouse encodes a novel member of
    the recA/RAD51 family.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. Original identification of XRCC2 as a recA/RAD51-family DNA-repair gene;
      testis-elevated expression suggests a meiotic role. Supports DNA repair and meiotic cell
      cycle annotations.
- id: Reactome:R-HSA-5685318
  title: BCDX2 complex formation
  findings: []
- id: Reactome:R-HSA-5685341
  title: BCDX2 complex stabilizes RAD51 filament
  findings: []
- id: Reactome:R-HSA-5685838
  title: CX3 complex binds D-loop structures
  findings: []
- id: Reactome:R-HSA-5686410
  title: BLM mediates dissolution of double Holliday junction
  findings: []
- id: Reactome:R-HSA-5686440
  title: MUS81:EME1,EME2 cleaves D-loop
  findings: []
- id: Reactome:R-HSA-5686469
  title: Resolution of D-loops cleaved by MUS81:EME1 or MUS81:EME2
  findings: []
- id: Reactome:R-HSA-5686483
  title: Resolution of Holliday junctions cleaved by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)
  findings: []
- id: Reactome:R-HSA-5693539
  title: Ligation of DNA and formation of Holliday structures following repair synthesis
  findings: []
- id: Reactome:R-HSA-5693584
  title: Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)
  findings: []
- id: Reactome:R-HSA-5693589
  title: D-loop dissociation and strand annealing
  findings: []
- id: Reactome:R-HSA-5693593
  title: D-loop extension by DNA polymerases
  findings: []
- id: Reactome:R-HSA-5693620
  title: D-loop formation mediated by PALB2, BRCA2 and RAD51
  findings: []
- id: Reactome:R-HSA-9701199
  title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
    of BRCA1 in PALB2 binding
  findings: []
- id: Reactome:R-HSA-9704330
  title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
    of PALB2 in BRCA1 binding
  findings: []
- id: Reactome:R-HSA-9704408
  title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
    of PALB2 in binding to BRCA2/RAD51/RAD51C
  findings: []
- id: Reactome:R-HSA-9709601
  title: Defective recruitment of BRCA2 and RAD51 due to loss of BRCA2 function in
    PALB2 binding
  findings: []
- id: Reactome:R-HSA-9853389
  title: FIGNL1 binds RAD51
  findings: []