id: O43502
gene_symbol: RAD51C
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RAD51C (RAD51 paralog C; RAD51L2; DNA repair protein RAD51 homolog 3; FANCO) is one of
  five human RAD51 paralogs and the only one shared between the two paralog complexes:
  BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). It is a RecA/RAD51-family
  protein with Walker A/B nucleotide-binding motifs that binds single-stranded DNA and
  branched DNA structures such as replication forks and Holliday junctions. Within its
  complexes it acts as a mediator of homologous recombination: through coupled ATP binding
  and hydrolysis it promotes nucleation and extension of the RAD51 recombinase nucleoprotein
  filament on RPA-coated single-stranded DNA. BCDX2 acts early, downstream of BRCA2 and
  upstream of RAD51 loading, to assemble and stabilize RAD51 filaments and to protect and
  restart stalled replication forks; CX3 acts later, binding D-loop and Holliday-junction
  intermediates and promoting branch migration and resolution. RAD51C is required for
  repair of DNA double-strand breaks and interstrand crosslinks, for RAD51 focus formation,
  sister chromatid cohesion, and genome stability. It also accumulates at damage sites
  (dependent on ATM, NBS1 and RPA) and facilitates activation of the CHK2 checkpoint kinase,
  coupling damage sensing to cell-cycle arrest. Additional reported roles include maintenance
  of mitochondrial DNA copy number under oxidative stress and meiotic recombination.
  Biallelic loss of function causes a Fanconi anemia-like disorder (complementation group O,
  FANCO); monoallelic germline mutations predispose to hereditary breast and ovarian cancer
  (BROVCA3).
alternative_products:
- name: '1'
  id: O43502-1
- name: '2'
  id: O43502-2
  sequence_note: VSP_043656, VSP_043657
existing_annotations:
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      RAD51C-containing paralog complexes (BCDX2 and CX3) localize to and act at replication
      forks. Well supported by direct EM visualization of both complexes bound to forked DNA.
    action: ACCEPT
    reason: >-
      Consistent with experimental evidence that BCDX2 and CX3 bind replication-fork DNA and
      function in fork protection/restart. The IBA localization is at an appropriate level.
    supported_by:
    - reference_id: PMID:20207730
      supporting_text: binding of BCDX2 and CX3 to DNA templates containing replication forks and
- term:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: >-
      RAD51C participates in Holliday-junction branch migration and resolution as part of
      CX3, but it is a RecA-fold ATPase mediator with no nuclease catalytic residues; the
      endonucleolytic cleavage activity itself is not a molecular function of RAD51C.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Depletion of RAD51C reduces branch migration and HJ resolvase activity in extracts
      (PMID:14716019), but the actual endonuclease/resolvase catalysis was subsequently
      attributed to GEN1 acting with XRCC3; RAD51C contributes to processing without itself
      catalyzing junction cleavage. Assigning the endonuclease molecular function to RAD51C
      (even with contributes_to) over-annotates its biochemistry. Its role in HJ processing
      is better captured by DNA recombination / DSB-repair-via-HR terms.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      - PSEUDO_OR_SUBACTIVITY_LOSS
    supported_by:
    - reference_id: PMID:23108668
      supporting_text: XRCC3 functions jointly with GEN1 later
    - reference_id: PMID:23108668
      supporting_text: at the stage of Holliday junction resolution
- term:
    id: GO:0033065
    label: Rad51C-XRCC3 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      RAD51C is a subunit of the CX3 complex (RAD51C-XRCC3). Directly demonstrated by
      complex purification.
    action: ACCEPT
    reason: >-
      Core, well-established complex membership supported by biochemical purification.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: the five paralogs exist in two distinct complexes in human cells
- term:
    id: GO:0000400
    label: four-way junction DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: >-
      RAD51C-containing complexes bind Holliday junctions (four-way junctions) with high
      specificity, as visualized by EM.
    action: ACCEPT
    reason: >-
      Direct experimental support; contributes_to is appropriate since binding is a property
      of the assembled paralog complex.
    supported_by:
    - reference_id: PMID:20207730
      supporting_text: both complexes bind with exceptionally high specificity to the DNA junctions
- term:
    id: GO:0000707
    label: meiotic DNA recombinase assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      RAD51 paralogs promote recombinase (RAD51/DMC1) filament assembly, including in meiosis;
      inferred phylogenetically from yeast Rad55/Rad57-type mediators and supported by the
      mammalian mediator role in RAD51 filament assembly.
    action: KEEP_AS_NON_CORE
    reason: >-
      Meiotic recombinase assembly is a plausible conserved role, but for human RAD51C the
      dominant, experimentally characterized function is mitotic/somatic HR mediation. Retained
      as a non-core, meiosis-specific function. Supported in the mouse ortholog: hypomorphic
      Rad51c spermatocytes arrest in early meiotic prophase I, evidencing a role in early
      RAD51-mediated (recombinase-assembly) meiotic recombination.
    supported_by:
    - reference_id: PMID:17312021
      supporting_text: providing evidence for the role of RAD51C in early stages of RAD51-mediated
        recombination
- term:
    id: GO:0007131
    label: reciprocal meiotic recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred meiotic crossover recombination role, consistent with the
      RAD51 paralog family's function in recombination.
    action: KEEP_AS_NON_CORE
    reason: >-
      Legitimate conserved meiotic role but not the core somatic HR-mediator function that
      defines human RAD51C. Kept as non-core. Corroborated by mouse data: RAD51C localizes to
      meiotic chromosomes and the RAD51C-XRCC3 resolvase complex associates with crossovers,
      resolving recombination intermediates before chromosome segregation.
    supported_by:
    - reference_id: PMID:17114795
      supporting_text: associates with crossovers and may play an essential role in the resolution
        of recombination intermediates prior to chromosome segregation
- term:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      RAD51C is a subunit of the BCDX2 complex (RAD51B-RAD51C-RAD51D-XRCC2).
    action: ACCEPT
    reason: >-
      Core complex membership, directly demonstrated by purification and cryo-EM.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: the five paralogs exist in two distinct complexes in human cells
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      RAD51C (within BCDX2/CX3) binds single-stranded, branched and duplex DNA. The generic
      DNA-binding term is accurate though broad.
    action: ACCEPT
    reason: >-
      Supported by biochemical DNA-binding data for the complexes; a valid parent term. More
      specific activities (ssDNA binding, four-way junction binding) are captured separately.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: BCDX2 binds single-stranded DNA and single-stranded gaps in duplex DNA
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      RAD51C has a Walker A/B P-loop (residues 125-132) and binds ATP; ATP binding/hydrolysis
      is essential for its mediator function.
    action: ACCEPT
    reason: >-
      Supported by conserved Walker motifs and by functional requirement of the ATP-binding
      domain (K131 mutagenesis) for RAD51C activity.
    supported_by:
    - reference_id: PMID:12966089
      supporting_text: reduced homology-directed repair of a DNA double-strand break by gene
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: RAD51C is a nuclear protein acting in nuclear HR; also has cytoplasmic pools.
    action: ACCEPT
    reason: Consistent with GFP-tagging and immunofluorescence localizing RAD51C to the nucleus.
    supported_by:
    - reference_id: PMID:12966089
      supporting_text: the protein is localized
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      A cytoplasmic/perinuclear pool of RAD51C exists and regulates RAD51 stability; damage
      induces nuclear redistribution.
    action: ACCEPT
    reason: Supported by detection of endogenous cytoplasmic Rad51C.
    supported_by:
    - reference_id: PMID:16215984
      supporting_text: detect endogenous Rad51C
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      RAD51C is present in human mitochondria, where it (with RAD51 and XRCC3) maintains mtDNA
      copy number under oxidative stress.
    action: ACCEPT
    reason: Directly demonstrated mitochondrial localization; a genuine non-core localization.
    supported_by:
    - reference_id: PMID:20413593
      supporting_text: Rad51 and the related HR proteins Rad51C and Xrcc3 exist in human mitochondria
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: RAD51C is essential for DNA repair, principally via homologous recombination.
    action: ACCEPT
    reason: Broad but accurate parent; captured more specifically by DSB-repair-via-HR.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      A perinuclear cytoplasmic pool of RAD51C is observed; this is a peripheral localization
      relative to its core nuclear HR function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by localization studies but not part of the core HR-mediator activity.
    supported_by:
    - reference_id: PMID:16215984
      supporting_text: detect endogenous Rad51C
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:11751636
  qualifier: contributes_to
  review:
    summary: >-
      Proposed new annotation. The Rad51B-Rad51C complex has directly demonstrated ssDNA
      binding and ssDNA-stimulated ATPase activity, which is the substrate-engagement half of
      the recombination-mediator role. contributes_to, because the activity is measured on the
      complex rather than on RAD51C alone.
    action: NEW
    reason: >-
      Licenses the molecular function assigned to core function 1. That core function describes
      the RAD51-filament mediator role on RPA-coated ssDNA, and its supporting quotes are all
      ssDNA-context results with no four-way junction in them, so GO:0000400 (correct for core
      functions 2 and 3, which do rest on junction-binding specificity) was the wrong term
      there. The mediator activity itself has no GO molecular function - see proposed_new_terms.
    supported_by:
    - reference_id: PMID:11751636
      supporting_text: >-
        Rad51B-Rad51C complex has ssDNA binding and ssDNA-stimulated ATPase activities
- 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-derived electronic assignment of a damage-sensor activity. RAD51C does bind
      branched DNA and does have an ssDNA-stimulated ATPase, but the term denotes a molecule
      that "recognises toxic DNA structures, and initiates a signaling response, driven by ATP
      hydrolysis" - a sensor. RAD51C's demonstrated activity is loading RAD51 onto RPA-coated
      ssDNA; the CHK2 requirement is a downstream genetic dependency, not a demonstrated
      signal-initiating activity of RAD51C itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagation of a RecA/RAD51-family ATPase/damage-sensor function, the same call the
      sibling XRCC2 review makes for the identical InterPro-derived row. It is not used by any
      core function here: the mediator activity it was standing in for has no GO term, and is
      filed under proposed_new_terms instead. The DNA-binding contributions RAD51C does make
      are carried by GO:0003697 and GO:0000400.
    supported_by:
    - reference_id: PMID:19451272
      supporting_text: an early function of RAD51C in DNA repair in facilitating phosphorylation of the checkpoint kinase CHK2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11751635
  qualifier: enables
  review:
    summary: >-
      Captures interaction with RAD51B (BCDX2 subunit). Real interaction but the generic
      protein-binding term is uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, protein binding (GO:0005515) is uninformative as a molecular
      function. The specific, meaningful relationship (BCDX2 complex membership) is captured by
      GO:0033063 and the core functions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11842113
  qualifier: enables
  review:
    summary: Captures paralog interactions (RAD51B/RAD51D/XRCC2/XRCC3). Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real interactions, but generic protein binding is uninformative; complex membership is
      captured by GO:0033063 and GO:0033065.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16395335
  qualifier: enables
  review:
    summary: Captures RAD51 interaction. Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Interaction with RAD51 underlies the mediator function, which is better represented by
      the HR-mediator core functions rather than generic protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21965664
  qualifier: enables
  review:
    summary: Captures SWSAP1 interaction (HR repair). Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative; interaction noted in the description.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24005329
  qualifier: enables
  review:
    summary: Captures HELQ/XRCC3 interactions. Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative as a molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24141787
  qualifier: enables
  review:
    summary: >-
      Captures the PALB2/BRCA2/RAD51 HR-complex interactions. Real and important, but the
      generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      RAD51C is part of a PALB2-BRCA2-RAD51 HR complex; this is described in the gene summary
      but generic protein binding is not an informative molecular function.
    supported_by:
    - reference_id: PMID:24141787
      supporting_text: part of a novel protein complex that contains PALB2 and BRCA2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: High-throughput interactome (XRCC3). Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from high-throughput data; uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome (XRCC2). Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from high-throughput data; uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28864920
  qualifier: enables
  review:
    summary: Captures RAD51B/XRCC3 interactions. Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative as a molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput interactome (RAD51B/XRCC2/RAD51D). Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from proteome-scale data; uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591612
  qualifier: enables
  review:
    summary: Breast-cancer interactome (RAD51B/XRCC3). Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from high-throughput data; uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome (RAD51B/RAD51D). Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from high-throughput data; uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9469824
  qualifier: enables
  review:
    summary: >-
      Original yeast two-hybrid interactions with XRCC3 and RAD51B. Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Historical two-hybrid interactions; generic protein binding is uninformative and the
      paralog relationships are captured by complex terms.
    supported_by:
    - reference_id: PMID:9469824
      supporting_text: Rad51C protein binds to two other
- term:
    id: GO:0000722
    label: telomere maintenance via recombination
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      RAD51 paralogs contribute to recombination-based telomere maintenance (ALT). Inferred by
      orthology from mouse.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible peripheral role via the general HR machinery, but not a distinctively
      characterized core function of human RAD51C. Retained as non-core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: RAD51C localizes to the nucleoplasm (immunofluorescence, HPA).
    action: ACCEPT
    reason: Consistent with nuclear HR function; direct immunofluorescence evidence.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Mitochondrial localization (immunofluorescence, HPA), consistent with mtDNA role.
    action: ACCEPT
    reason: Corroborates the experimentally demonstrated mitochondrial pool of RAD51C.
    supported_by:
    - reference_id: PMID:20413593
      supporting_text: Rad51 and the related HR proteins Rad51C and Xrcc3 exist in human mitochondria
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Cytosolic pool of RAD51C detected by immunofluorescence (HPA).
    action: ACCEPT
    reason: Consistent with reported cytoplasmic/perinuclear pools regulating RAD51 stability.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: NAS
  original_reference_id: PMID:26354865
  qualifier: involved_in
  review:
    summary: >-
      RAD51C is required for HR repair of DNA double-strand breaks; this is its core biological
      process.
    action: ACCEPT
    reason: >-
      Central, well-established function supported across many studies (mediator of RAD51
      filament assembly required for HR).
    supported_by:
    - reference_id: PMID:37344587
      supporting_text: BCDX2 stimulates the nucleation and extension of RAD51
- term:
    id: GO:0031297
    label: replication fork processing
  evidence_type: IDA
  original_reference_id: PMID:26354865
  qualifier: involved_in
  review:
    summary: >-
      RAD51C protects nascent DNA at stalled forks and promotes replication restart in an
      ATP-hydrolysis-dependent manner.
    action: ACCEPT
    reason: >-
      Directly demonstrated: RAD51C/XRCC3 prevent nascent-DNA degradation and restart halted
      forks; patient mutations abrogate fork protection.
    supported_by:
    - reference_id: PMID:26354865
      supporting_text: RAD51C and XRCC3 promote the restart of stalled replication
    - reference_id: PMID:26354865
      supporting_text: extensive degradation of nascent DNA at stalled
- term:
    id: GO:0033065
    label: Rad51C-XRCC3 complex
  evidence_type: IPI
  original_reference_id: PMID:11751635
  qualifier: part_of
  review:
    summary: CX3 complex membership, established by co-purification with XRCC3.
    action: ACCEPT
    reason: Core complex membership; direct biochemical evidence.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: the five paralogs exist in two distinct complexes in human cells
- term:
    id: GO:0043596
    label: nuclear replication fork
  evidence_type: IDA
  original_reference_id: PMID:26354865
  qualifier: located_in
  review:
    summary: RAD51C localizes to nuclear replication forks (nascent DNA) upon fork stalling.
    action: ACCEPT
    reason: Directly demonstrated recruitment to stalled forks/nascent DNA.
    supported_by:
    - reference_id: PMID:26354865
      supporting_text: extensive degradation of nascent DNA at stalled
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: NAS
  original_reference_id: PMID:32669601
  qualifier: located_in
  review:
    summary: RAD51C-containing paralog complexes act at replication forks during remodeling/restart.
    action: ACCEPT
    reason: Consistent with fork localization and function; corroborated by EM and fork-protection studies.
    supported_by:
    - reference_id: PMID:32669601
      supporting_text: RAD51 paralogs as important modulators of RAD51 foci formation upon mild replication stress
- term:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
  evidence_type: IPI
  original_reference_id: PMID:11751635
  qualifier: part_of
  review:
    summary: BCDX2 complex membership, established by co-purification.
    action: ACCEPT
    reason: Core complex membership; direct biochemical evidence.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: the five paralogs exist in two distinct complexes in human cells
- term:
    id: GO:0097435
    label: supramolecular fiber organization
  evidence_type: IDA
  original_reference_id: PMID:37344587
  qualifier: involved_in
  review:
    summary: >-
      As part of BCDX2, RAD51C promotes nucleation and extension of the RAD51 nucleoprotein
      filament (a supramolecular fiber) in an ATP-hydrolysis-dependent manner. This captures
      the core mediator function.
    action: MODIFY
    reason: >-
      Directly demonstrated by cryo-EM and single-molecule assays that BCDX2 stimulates RAD51
      filament nucleation/extension via coupled RAD51B/RAD51C ATPases, but supramolecular fiber
      organization is a generic parent.
      GO:0000730 DNA recombinase assembly - "the aggregation, arrangement and bonding together
      of strand exchange proteins (recombinases) into higher order oligomers on single-stranded
      DNA" - is literally what this experiment shows, and is the term this same PR uses for
      RAD51. The generic supramolecular-fiber parent loses the recombinase identity, which is
      the whole content of the finding.
    proposed_replacement_terms:
    - id: GO:0000730
      label: DNA recombinase assembly
    supported_by:
    - reference_id: PMID:37344587
      supporting_text: BCDX2 stimulates the nucleation and extension of RAD51
    - reference_id: PMID:37344587
      supporting_text: BCDX2 promotes RAD51 filament nucleation and growth in an ATP hydrolysis dependent manner
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35849344
  qualifier: enables
  review:
    summary: Captures interaction with the DDUP microprotein in the DNA damage response. Uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative as a molecular function.
- 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 and CX3 bind four-way (Holliday) junctions with high
      specificity.
    action: ACCEPT
    reason: >-
      Strong experimental support; contributes_to reflects that binding is a property of the
      assembled complex.
    supported_by:
    - reference_id: PMID:20207730
      supporting_text: both complexes bind with exceptionally high specificity to the DNA junctions
    - reference_id: PMID:20207730
      supporting_text: revealed a multimeric ring structure whose subunits are arranged into a flat disc around a central channel
- 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: >-
      RAD51C (in BCDX2 and CX3) is required for HR at defined steps: BCDX2 downstream of BRCA2
      and upstream of RAD51 loading, CX3 downstream of RAD51.
    action: ACCEPT
    reason: >-
      Experimental epistasis analysis places both RAD51C complexes within the BRCA-dependent HR
      pathway. Core function.
    supported_by:
    - reference_id: PMID:23149936
      supporting_text: act at different stages of the HR pathway
    - 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/CX3 bind replication-fork DNA (direct EM visualization).
    action: ACCEPT
    reason: Directly demonstrated binding to forked DNA templates.
    supported_by:
    - reference_id: PMID:20207730
      supporting_text: binding of BCDX2 and CX3 to DNA templates containing replication forks and
- term:
    id: GO:0008821
    label: crossover junction DNA endonuclease activity
  evidence_type: IMP
  original_reference_id: PMID:14716019
  qualifier: contributes_to
  review:
    summary: >-
      RAD51C depletion reduces Holliday-junction branch migration and resolvase activity in
      human extracts, but RAD51C is a RecA-fold ATPase mediator with no nuclease active site;
      the resolvase catalysis is contributed by GEN1, not RAD51C.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The experimental result (PMID:14716019) shows RAD51C is required for HJ processing
      activity in extracts, which the annotation reasonably reflects with contributes_to.
      However, subsequent work assigned the actual endonucleolytic resolution to GEN1 (acting
      with XRCC3); RAD51C promotes branch migration/resolution without possessing endonuclease
      activity itself. Attributing this catalytic molecular function to RAD51C is an
      over-annotation. Not removed, since the paper's experimental support is genuine.
    supported_by:
    - reference_id: PMID:14716019
      supporting_text: depletion of RAD51C from
    - reference_id: PMID:14716019
      supporting_text: caused a loss of branch migration and
    - reference_id: PMID:23108668
      supporting_text: XRCC3 functions jointly with GEN1 later
- term:
    id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:23108668
  qualifier: involved_in
  review:
    summary: >-
      RAD51B/RAD51C depletion induces G2/M arrest; RAD51C normally supports mitotic progression
      by completing recombinational repair and protecting against mitotic defects/aneuploidy.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported (IMP), but this cell-cycle effect is largely a downstream
      consequence of RAD51C's HR/repair role rather than a distinct core molecular function.
      Retained as non-core.
    supported_by:
    - reference_id: PMID:23108668
      supporting_text: inhibition of RAD51B or RAD51C induces
- term:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
  evidence_type: IDA
  original_reference_id: PMID:11751635
  qualifier: part_of
  review:
    summary: BCDX2 complex membership (direct isolation/purification).
    action: ACCEPT
    reason: Core complex membership; direct experimental evidence.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: the five paralogs exist in two distinct complexes in human cells
- term:
    id: GO:0033065
    label: Rad51C-XRCC3 complex
  evidence_type: IDA
  original_reference_id: PMID:11751635
  qualifier: part_of
  review:
    summary: CX3 complex membership (direct isolation/purification).
    action: ACCEPT
    reason: Core complex membership; direct experimental evidence.
    supported_by:
    - reference_id: PMID:11751635
      supporting_text: the five paralogs exist in two distinct complexes in human cells
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685318
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome, BCDX2 complex formation).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685319
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome, CX3 complex formation).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685341
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome, BCDX2 stabilizes RAD51 filament).
    action: ACCEPT
    reason: Consistent with 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 (Reactome, CX3 binds D-loop structures).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686410
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686440
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686469
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686483
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693539
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693584
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693589
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693593
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693620
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome, D-loop formation by PALB2/BRCA2/RAD51).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9701199
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9704330
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9704408
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709601
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983218
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome, RAD51B:RAD51C binds ssDNA).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983285
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome, RAD51B binds RAD51C).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9853389
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (Reactome HR pathway step).
    action: ACCEPT
    reason: Consistent with nuclear HR function.
- term:
    id: GO:0007062
    label: sister chromatid cohesion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      RAD51C contributes to sister chromatid cohesion (UniProt), inferred by sequence similarity
      from mouse ortholog and directly supported by hamster RAD51C-mutant (CL-V4B) cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      A reported contributory role but peripheral to the core HR-mediator function; kept as
      non-core. Experimentally corroborated: RAD51C-deficient CL-V4B cells show reduced sister
      chromatid cohesion, complemented by Rad51C cDNA.
    supported_by:
    - reference_id: PMID:12000837
      supporting_text: reduced level of sister chromatid cohesion was found in CL-V4B cells
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12966089
  qualifier: located_in
  review:
    summary: GFP-tagged RAD51L2/RAD51C localizes to the nucleus; a C-terminal NLS is identified.
    action: ACCEPT
    reason: Direct experimental localization to the nucleus.
    supported_by:
    - reference_id: PMID:12966089
      supporting_text: the protein is localized
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16215984
  qualifier: located_in
  review:
    summary: Endogenous RAD51C detected in the nucleus; nuclear levels increase after DNA damage.
    action: ACCEPT
    reason: Direct experimental localization.
    supported_by:
    - reference_id: PMID:16215984
      supporting_text: detect endogenous Rad51C
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16215984
  qualifier: located_in
  review:
    summary: Endogenous RAD51C detected in the cytoplasm; regulates RAD51 proteolysis.
    action: ACCEPT
    reason: Directly demonstrated cytoplasmic pool.
    supported_by:
    - reference_id: PMID:16215984
      supporting_text: important role in regulating this process
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IDA
  original_reference_id: PMID:19451272
  qualifier: involved_in
  review:
    summary: >-
      RAD51C has an early DNA-repair function facilitating CHK2 phosphorylation and damage-signal
      transduction leading to cell-cycle arrest and HR activation.
    action: ACCEPT
    reason: Direct experimental evidence for a DNA-repair/damage-response function of RAD51C.
    supported_by:
    - reference_id: PMID:19451272
      supporting_text: an early function of RAD51C in DNA repair in facilitating phosphorylation of the checkpoint kinase CHK2
- term:
    id: GO:0000077
    label: DNA damage checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:19451272
  qualifier: involved_in
  review:
    summary: >-
      Proposed new annotation. RAD51C accumulates at DNA-damage sites (ATM-, NBS1- and
      RPA-dependent) and is required for phosphorylation of the checkpoint kinase CHK2,
      transducing the damage signal that enforces S and G2/M arrest. GOA captures this only as
      the generic GO:0006281 DNA repair, which does not describe checkpoint transduction.
    action: NEW
    reason: >-
      Checkpoint signalling is a distinct process from the repair reaction itself, and the same
      reference that supports the GO:0006281 row demonstrates the CHK2 arm specifically. Added so
      that the corresponding core function has a process term that matches what it describes;
      FANCM in this same cohort already carries GO:0000077 for equivalent evidence, and with the
      same code. Evidence is IMP, not IDA: the CHK2 result rests on siRNA depletion of RAD51C
      ("cells depleted of RAD51C"), which is a mutant/altered-gene-product phenotype. GOA codes
      its GO:0006281 row on this PMID as IDA, but that is a curator's choice and not one to
      restate as our own on an author-supplied annotation.
    supported_by:
    - reference_id: PMID:19451272
      supporting_text: an early function of RAD51C in DNA repair in facilitating phosphorylation of the checkpoint kinase CHK2
- term:
    id: GO:0006310
    label: DNA recombination
  evidence_type: IDA
  original_reference_id: PMID:19451272
  qualifier: involved_in
  review:
    summary: >-
      RAD51C acts in the homologous recombination pathway, accumulating at damage sites with an
      early and late role.
    action: ACCEPT
    reason: >-
      Supported by RAD51C's recruitment kinetics and mediator role in HR; DNA recombination is
      an accurate parent term.
    supported_by:
    - reference_id: PMID:19451272
      supporting_text: The kinetics of RAD51C recruitment is consistent with both an early and a late role in HR
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16215984
  qualifier: located_in
  review:
    summary: RAD51C is detected in a perinuclear cytoplasmic region.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported peripheral localization, not part of the core nuclear HR-mediator function.
    supported_by:
    - reference_id: PMID:16215984
      supporting_text: detect endogenous Rad51C
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:20413593
  qualifier: located_in
  review:
    summary: >-
      RAD51C is present in human mitochondria and maintains mtDNA copy number under oxidative
      stress (with RAD51 and XRCC3).
    action: ACCEPT
    reason: Directly demonstrated mitochondrial localization and function.
    supported_by:
    - reference_id: PMID:20413593
      supporting_text: Depletion of Rad51, Rad51C, or Xrcc3 results in a dramatic decrease in mtDNA copy number
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: TAS
  original_reference_id: PMID:9469824
  qualifier: enables
  review:
    summary: >-
      RAD51C is a RAD51-family strand-exchange-related protein reported to bind DNA; the
      complexes it forms bind ssDNA/branched/duplex DNA.
    action: ACCEPT
    reason: Accurate broad molecular function; corroborated by biochemical DNA-binding of BCDX2/CX3.
    supported_by:
    - reference_id: PMID:9469824
      supporting_text: recombinational repair of DNA damage and meiotic
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:9469824
  qualifier: located_in
  review:
    summary: RAD51C is a nuclear DNA-repair/recombination protein.
    action: ACCEPT
    reason: Consistent with all subsequent localization data.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: TAS
  original_reference_id: PMID:9469824
  qualifier: involved_in
  review:
    summary: RAD51C functions in recombinational repair of DNA damage.
    action: ACCEPT
    reason: Accurate broad DNA-repair role; well supported by the whole literature.
    supported_by:
    - reference_id: PMID:9469824
      supporting_text: recombinational repair of DNA damage and meiotic
- term:
    id: GO:0006310
    label: DNA recombination
  evidence_type: TAS
  original_reference_id: PMID:9469824
  qualifier: involved_in
  review:
    summary: RAD51C is a member of the RAD51 recombination family involved in DNA recombination.
    action: ACCEPT
    reason: Accurate broad recombination role.
    supported_by:
    - reference_id: PMID:9469824
      supporting_text: recombinational repair of DNA damage and meiotic
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IMP
  original_reference_id: PMID:20400963
  qualifier: involved_in
  review:
    summary: >-
      RAD51C is the Fanconi anemia complementation group O (FANCO) gene; biallelic loss of
      function causes an FA-like disorder with hypersensitivity to DNA interstrand cross-linking
      agents (mitomycin C, cisplatin). RAD51C acts downstream in the ICL-repair pathway (via
      homologous recombination), not in ICL unhooking or FANCD2 monoubiquitination. This specific
      process is only captured broadly by DNA repair / DSB-repair-via-HR in the existing GOA set.
    action: NEW
    reason: >-
      Interstrand cross-link repair is a core, defining, well-evidenced function of RAD51C
      (FANCO): patient/mutant cells are hypersensitive to ICL agents and biallelic mutation
      causes a Fanconi anemia-like syndrome. GO:0036297 is the appropriate specific biological
      process term (active BP, verified via QuickGO), more precise than the existing GO:0006281
      DNA repair parent.
    supported_by:
    - reference_id: PMID:20400963
      supporting_text: increased cellular sensitivity to the DNA interstrand cross-linking agent
        mitomycin C and the topoisomerase-1 inhibitor camptothecin
    - reference_id: PMID:20400963
      supporting_text: biallelic germline mutations in a RAD51 paralog are associated with an
        FA-like syndrome
core_functions:
- description: >-
    As a subunit of the BCDX2 complex (RAD51B-RAD51C-RAD51D-XRCC2), RAD51C binds
    single-stranded and branched DNA and, through the coupled ATP-binding/hydrolysis activity
    of RAD51B and RAD51C, acts as a recombination mediator that promotes nucleation and
    extension of the RAD51 recombinase nucleoprotein filament on RPA-coated ssDNA. This
    early (downstream of BRCA2, upstream of RAD51 loading) step is required for homologous
    recombination repair of DNA double-strand breaks and interstrand crosslinks.
  supported_by:
  - reference_id: PMID:37344587
    supporting_text: BCDX2 stimulates the nucleation and extension of RAD51
  - reference_id: PMID:23149936
    supporting_text: the BCDX2 complex acts downstream of BRCA2 recruitment but
  - reference_id: PMID:11751636
    supporting_text: The competition by RPA for substrate binding can be partially
      alleviated by Rad51B-Rad51C
  contributes_to_molecular_function:
    id: GO:0003697
    label: single-stranded DNA binding
  directly_involved_in:
  - id: GO:0000730
    label: DNA recombinase assembly
  - id: GO:0000724
    label: double-strand break repair via homologous recombination
  - id: GO:0006281
    label: DNA repair
  locations:
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
- description: >-
    RAD51C-containing paralog complexes bind replication-fork and Holliday-junction DNA with
    high specificity via four-way junction DNA binding, protecting nascent DNA at stalled
    forks and promoting ATP-hydrolysis-dependent replication restart, thereby preventing
    fork collapse and preserving genome stability.
  supported_by:
  - reference_id: PMID:20207730
    supporting_text: both complexes bind with exceptionally high specificity to the DNA junctions
  - reference_id: PMID:26354865
    supporting_text: RAD51C and XRCC3 promote the restart of stalled replication
  contributes_to_molecular_function:
    id: GO:0000400
    label: four-way junction DNA binding
  directly_involved_in:
  - id: GO:0031297
    label: replication fork processing
  locations:
  - id: GO:0043596
    label: nuclear replication fork
  - id: GO:0005657
    label: replication fork
  in_complex:
    id: GO:0033063
    label: Rad51B-Rad51C-Rad51D-XRCC2 complex
- description: >-
    Within the CX3 complex (RAD51C-XRCC3), RAD51C acts late in homologous recombination,
    binding D-loop and Holliday-junction intermediates and promoting branch migration and
    resolution of recombination intermediates (downstream of RAD51 loading).
  supported_by:
  - reference_id: PMID:23149936
    supporting_text: act at different stages of the HR pathway
  - reference_id: PMID:14716019
    supporting_text: caused a loss of branch migration and
  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:0006310
    label: DNA recombination
  locations:
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:0033065
    label: Rad51C-XRCC3 complex
- description: >-
    RAD51C accumulates at DNA-damage sites (dependent on ATM, NBS1 and RPA) and facilitates
    activation of the CHK2 checkpoint kinase, transducing the DNA-damage signal to enforce
    S and G2/M cell-cycle arrest and enable HR. Retained as a distinct core function from the
    RAD51-mediator role above because the contribution is deployed toward checkpoint signalling
    rather than toward filament formation; the process term is GO:0000077 DNA damage checkpoint
    signalling, not the generic GO:0006281 DNA repair, which does not describe checkpoint
    transduction. No molecular_function is asserted: the single supporting result is that CHK2
    phosphorylation requires RAD51C, which identifies neither a catalytic activity nor a binding
    partner for RAD51C itself. The GO:0140664 ATP-dependent DNA damage sensor term an earlier
    draft used here invokes ATP and structure recognition, neither of which this evidence
    addresses.
  supported_by:
  - reference_id: PMID:19451272
    supporting_text: an early function of RAD51C in DNA repair in facilitating phosphorylation of the checkpoint kinase CHK2
  directly_involved_in:
  - id: GO:0000077
    label: DNA damage checkpoint signaling
  locations:
  - id: GO:0005654
    label: nucleoplasm
proposed_new_terms:
- proposed_name: DNA recombinase loader activity
  proposed_definition: >-
    Binding to a DNA strand exchange protein (recombinase) and to single-stranded DNA so as to
    promote nucleation and extension of the recombinase nucleoprotein filament, including
    displacement of the single-stranded DNA-binding protein that otherwise occludes the
    substrate. The loader is not itself a strand exchange protein and does not catalyse strand
    exchange.
  justification: >-
    GO has the process term GO:0000730 DNA recombinase assembly but no molecular function for
    the activity that carries it out. That gap is why RAD51C's mediator role has been annotated
    with borrowed terms: an InterPro-derived IEA supplies GO:0140664 ATP-dependent DNA damage
    sensor activity, which describes a sensor rather than a loader and which the sibling XRCC2
    review in this same cohort marks as a RecA/RAD51-family over-propagation, while the
    alternative GO:0097435 supramolecular fiber organization is a generic parent that loses the
    recombinase identity entirely. The RAD51 paralog complexes BCDX2 and CX3 are the clearest
    use case - BCDX2 "stimulates the nucleation and extension of RAD51" on RPA-coated ssDNA in
    an ATP-hydrolysis-dependent manner - and the same term would serve BRCA2, RAD52 and the
    bacterial RecFOR and RecBCD loaders, none of which has a molecular function for this
    activity either.
  proposed_parent:
    id: GO:0003697
    label: single-stranded DNA binding
  supported_by:
  - reference_id: PMID:37344587
    supporting_text: BCDX2 stimulates the nucleation and extension of RAD51
  - reference_id: PMID:11751636
    supporting_text: The competition by RPA for substrate binding can be partially
      alleviated by Rad51B-Rad51C
suggested_questions:
- question: >-
    Does RAD51C possess intrinsic catalytic activity beyond ATP hydrolysis, or is its function
    entirely as a DNA-binding, RAD51-filament mediator within BCDX2 and CX3?
- question: >-
    What is the mechanistic basis by which RAD51C is required for CHK2 activation - a direct
    scaffolding role at damage sites or an indirect consequence of HR intermediate processing?
suggested_experiments:
- description: >-
    Structure-guided separation-of-function mutants that uncouple RAD51C ssDNA binding, ATP
    hydrolysis, and RAD51-filament stimulation, tested for HR, fork protection, and checkpoint
    signaling.
- description: >-
    Reconstituted assays with purified CX3 to define whether RAD51C/XRCC3 directly drive branch
    migration independently of GEN1-mediated junction cleavage.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- 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: >-
      PubMed/PMC-verified. Establishes the two RAD51C-containing complexes (BCDX2 and CX3) by
      purification and shows BCDX2 binds ssDNA, ss gaps and nicks. Foundational for the complex
      and DNA-binding annotations.
- id: PMID:11751636
  title: Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed
    DNA strand exchange.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified (PubMed abstract). Original biochemical demonstration that the RAD51B-RAD51C
      complex has ssDNA-binding and ssDNA-stimulated ATPase activity and acts as a recombination
      mediator by partially relieving RPA competition for ssDNA, promoting RAD51-ssDNA filament
      assembly. Primary support for the BCDX2 HR-mediator core function (previously supported only
      by the later cryo-EM and epistasis papers).
- id: PMID:11842113
  title: Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs
    in human cells.
  findings: []
- id: PMID:12000837
  title: Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid
    cohesion and genomic stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified (PMC full text). RAD51C-mutant hamster CL-V4B cells show cross-link (MMC/cisplatin)
      hypersensitivity, impaired RAD51 focus formation, genomic instability, and a reduced level
      of sister chromatid cohesion (complemented by Rad51C cDNA). Direct experimental support for
      the sister-chromatid-cohesion (GO:0007062) and ICL-repair annotations.
- id: PMID:12966089
  title: Identification of functional domains in the RAD51L2 (RAD51C) protein and
    its requirement for gene conversion.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. Shows RAD51C ATP-binding domain (K131) is required for function, nuclear
      localization with a C-terminal NLS, and a requirement for gene conversion (HR).
- id: PMID:14716019
  title: RAD51C is required for Holliday junction processing in mammalian cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified. RAD51C depletion reduces branch migration/HJ resolvase activity in extracts.
      Supports RAD51C's role in HJ processing, but the endonucleolytic catalysis was later
      attributed to GEN1; hence the crossover-junction endonuclease MF is marked over-annotated.
- id: PMID:16215984
  title: Cellular localization of human Rad51C and regulation of ubiquitin-mediated
    proteolysis of Rad51.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified. Detects endogenous RAD51C in nucleus, cytoplasm and perinuclear region and shows
      RAD51C regulates ubiquitin-mediated RAD51 proteolysis.
- id: PMID:16395335
  title: Interplay between human DNA repair proteins at a unique double-strand break
    in vivo.
  findings: []
- id: PMID:17114795
  title: Role of RAD51C and XRCC3 in genetic recombination and DNA repair.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified (PubMed abstract). Shows RAD51C localizes to mouse meiotic chromosomes at
      pachytene/diplotene and that Holliday-junction resolvase activity co-elutes with the CX3
      (RAD51C-XRCC3) complex, which associates with crossovers. Supports the non-core meiotic
      reciprocal-recombination annotation.
- id: PMID:17312021
  title: RAD51C deficiency in mice results in early prophase I arrest in males and
    sister chromatid separation at metaphase II in females.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified (PMC full text). Hypomorphic Rad51c mice show sexually dimorphic meiotic defects:
      early prophase I arrest in spermatocytes (early RAD51-mediated recombination role) and
      precocious sister-chromatid separation/aneuploidy in oocytes. Supports the non-core meiotic
      recombinase-assembly annotation.
- id: PMID:19451272
  title: RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified (PMC full text). Establishes RAD51C's early DDR role: recruitment dependent on
      ATM/NBS1/RPA and requirement for CHK2 activation and cell-cycle arrest.
- 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: >-
      Verified (PMC full text). Direct EM evidence that BCDX2 and CX3 bind Holliday junctions and
      replication forks with high specificity as ring-shaped complexes.
- id: PMID:20400963
  title: Mutation of the RAD51C gene in a Fanconi anemia-like disorder.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified (PubMed abstract). Identifies a homozygous RAD51C missense mutation in a
      consanguineous FA-like family, establishing RAD51C as the Fanconi anemia complementation
      group O (FANCO) gene; patient cells lose RAD51 focus formation and are hypersensitive to
      MMC and camptothecin. Primary support for the NEW interstrand-cross-link-repair (GO:0036297)
      annotation.
- id: PMID:20413593
  title: 'Discovery of a novel function for human Rad51: maintenance of the mitochondrial
    genome.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified. Demonstrates mitochondrial localization of RAD51C (with RAD51/XRCC3) and a role in
      maintaining mtDNA copy number under oxidative stress. Supports the non-core mitochondrial
      annotations.
- id: PMID:21965664
  title: hSWS1·SWSAP1 is an evolutionarily conserved complex required for efficient
    homologous recombination repair.
  findings: []
- id: PMID:23108668
  title: The RAD51 paralogs ensure cellular protection against mitotic defects and
    aneuploidy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified. RAD51B/RAD51C depletion causes G2/M arrest; XRCC3 acts with GEN1 at HJ resolution.
      Supports the non-core G2/M annotation and the reassignment of resolvase catalysis to GEN1.
- 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 (PMC). Epistasis places BCDX2 downstream of BRCA2/upstream of RAD51 and CX3
      downstream of RAD51 within BRCA-dependent HR. Core evidence for the DSB-repair-via-HR role.
- id: PMID:24005329
  title: HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and
    tumorigenesis.
  findings: []
- id: PMID:24141787
  title: Breast cancer-associated missense mutants of the PALB2 WD40 domain, which
    directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified. Shows RAD51C is part of a PALB2-BRCA2-containing HR complex and characterizes
      FANCO/BROVCA3 variants that disrupt these interactions.
- id: PMID:26354865
  title: Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate
    replication restart.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified (PMC full text). Directly demonstrates RAD51C protects nascent DNA at stalled forks
      and promotes ATP-hydrolysis-dependent restart; patient mutations abolish fork protection.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; supports a protein-binding IPI only (uninformative MF).
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; supports a protein-binding IPI only (uninformative MF).
- id: PMID:28864920
  title: Discovery of mutations in homologous recombination genes in African-American
    women with breast cancer.
  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: >-
      Supports the sequential action of RAD51 paralog complexes at replication forks and the
      replication-fork localization annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome; supports a protein-binding IPI only (uninformative MF).
- id: PMID:34591612
  title: A protein interaction landscape of breast cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; supports a protein-binding IPI only (uninformative MF).
- id: PMID:35849344
  title: LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling
    to trigger dual DNA repair mechanisms.
  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: >-
      Verified (PMC full text). Cryo-EM/biochemistry showing BCDX2 stimulates RAD51 filament
      nucleation and extension via coupled RAD51B/RAD51C ATPases. Key structural support for the
      RAD51-filament-mediator core function.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput cell-map interactome; supports a protein-binding IPI only.
- id: PMID:9469824
  title: Isolation and characterization of RAD51C, a new human member of the RAD51
    family of related genes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Verified. Original RAD51C isolation; family membership, testis-high expression, and Y2H
      interactions with XRCC3 and RAD51B. Supports the historical DNA-binding/repair/recombination
      TAS annotations.
- id: Reactome:R-HSA-5685318
  title: BCDX2 complex formation
  findings: []
- id: Reactome:R-HSA-5685319
  title: CX3 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-983218
  title: RAD51B:RAD51C binds single-stranded DNA
  findings: []
- id: Reactome:R-HSA-983285
  title: RAD51B binds RAD51C
  findings: []
- id: Reactome:R-HSA-9853389
  title: FIGNL1 binds RAD51
  findings: []