RAD51C (O43502) — review notes

Human RAD51C / RAD51L2 / R51H3 / FANCO. RAD51 paralog. 376 aa, chr17q. RecA family, RAD51 subfamily (UniProt SIMILARITY).

Core biology / provenance

• Only paralog shared by BOTH complexes: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3).
  PMID:11751635
  PMID:12966089

• BCDX2 binds ssDNA, ss gaps, nicks (early pre-RAD51 role):
  PMID:11751635

• Both complexes bind Holliday junctions and replication forks with high specificity; ring-shaped (four-way junction DNA binding; located at forks/junctions):
  PMID:20207730
  PMID:20207730

• BCDX2 = RAD51-filament mediator via coupled ATPases (cryo-EM, single molecule); RAD51 filament = supramolecular fiber:
  PMID:37344587
  PMID:37344587

• BCDX2 vs CX3 act at different HR stages:
  PMID:23149936

• HJ processing / branch migration & resolution (RAD51C/CX3, late HR). NOTE: RAD51C itself has no nuclease domain; the resolvase activity lost on RAD51C depletion is now attributed to GEN1 — RAD51C contributes to processing but is not itself an endonuclease:
  PMID:14716019
  PMID:23108668

• Early + late function; recruitment requires ATM/NBS1/RPA; required for CHK2 activation (checkpoint signaling):
  PMID:19451272
  PMID:19451272

• Gene conversion / HR-mediated DSB repair; nuclear localization; ATP-binding domain required:
  PMID:12966089
  PMID:12966089
  PMID:12966089

• Replication fork protection & restart (ATP-hydrolysis dependent); FANCO/BROVCA patient mutations fail to protect forks:
  PMID:26354865
  PMID:26354865

• Mitochondrial genome maintenance (Rad51/Rad51C/Xrcc3 in mitochondria; mtDNA copy number):
  PMID:20413593

• Regulates Rad51 stability (cytoplasmic/perinuclear pools; ubiquitin-mediated proteolysis of Rad51):
  PMID:16215984

• Mitotic protection: RAD51B/RAD51C depletion → G2/M arrest; paralogs protect against mitotic defects/aneuploidy:
  PMID:23108668

• PALB2-scaffolded HR complex (PALB2-BRCA2-RAD51C-RAD51):
  PMID:24141787

• SWSAP1 interaction (HR repair):
  PMID:21965664

Disease (UniProt)

• FANCO (Fanconi anemia complementation group O), biallelic; MIM:613390. His-258 variant characterized [PMID:20400963, PMID:24141787].
• BROVCA3 (familial breast-ovarian cancer 3), monoallelic; MIM:613399 [PMID:20400964, PMID:21990120, PMID:24141787].

Structure/features (UniProt)

• ATP BINDING 125..132 (Walker A). MUTAGEN K131A abolishes function/HJ resolution. Phospho-Ser20. NLS motif 366..370.
• 7 cryo-EM structures (BCDX2). RecA_ATP-bd IPR020588; Rad51_C IPR013632; PANTHER PTHR46239 RAD51C.

Curation decisions summary

• protein binding (GO:0005515, IPI ×15): MARK_AS_OVER_ANNOTATED (uninformative per guidelines; real interactors captured in complexes/core functions).
• crossover junction DNA endonuclease activity (GO:0008821, contributes_to, IBA+IMP): MARK_AS_OVER_ANNOTATED — RAD51C is a RecA-fold ATPase mediator, not a nuclease; resolvase activity reassigned to GEN1.
• Meiotic terms (GO:0000707, GO:0007131), telomere (GO:0000722), sister chromatid cohesion (GO:0007062), G2/M (GO:0010971), mitochondrion, perinuclear: KEEP_AS_NON_CORE.
• Core: HR mediator / RAD51 filament assembly (BCDX2), fork protection/restart, junction binding + late HR (CX3).