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).

2026-10-06 update: BCDX2 vs CX3 (trigger PMID:42682019)

Targeted update alongside the new XRCC3 review (genes/human/XRCC3/).
- Correction: core function 2 previously attributed ATP-hydrolysis-dependent fork restart to a
BCDX2-scoped core function. The review states fork protection involves both complexes
PMID:42682019,
while restart is CX3-specific PMID:42682019,
consistent with the primary data PMID:26354865.
Restart moved to the CX3 core function (added GO:0031297 there); description edited accordingly.
- New assemblies: RAD51C bridges XRCC3 and RAD51D-XRCC2 in X3CDX2, which caps RAD51 filaments
PMID:41196948;
independently DX2-CX3 / BCDX2-CX3 supercomplex PMID:41772053. No GO complex term exists for
X3CDX2 (added as a suggested question).
- No annotation actions were changed. The legacy MARK_AS_OVER_ANNOTATED actions on GO:0005515 were
left as-is (outside the scope of this targeted update).

2026-10-10 revision (PR #4409 review)

• All 14 GO:0005515 protein binding rows changed from MARK_AS_OVER_ANNOTATED to REMOVE, for
  consistency with the RAD51B, RAD51D and XRCC3 reviews: the generic term is uninformative, and the
  problem is lack of functional content, not a claim that exceeds the evidence. Removal does not
  dispute the interactions, which are captured by GO:0033063 / GO:0033065 and the core functions.
  This supersedes the note above that the legacy actions were left as-is.
• Completed the truncated PMID:41196948 quote ("...to promote homologous pairing").

2026-10-20 ORGANELLES batch 1 (mitochondrion rows)

• GO:0005739 rows: IEA GO_REF:0000044 ACCEPT (reason reworded and records the check: UniProt line is ECO:0000269 to
  PMID:20413593); IDA GO_REF:0000052 (HPA) ACCEPT; IDA PMID:20413593 ACCEPT. Actions unchanged.
• Added NEW GO:0042645 mitochondrial nucleoid, IDA PMID:29158291 (cached in this batch):
  PMID:29158291;
  PMID:29158291;
  PMID:29158291.
• PMID:20413593's protease-protection result ("Rad51 in the mitochondrial fraction is largely resistant to proteinase
  K treatment") is for RAD51 only, so it is not used for RAD51C.
• core_functions locations unchanged: the mitochondrial/nucleoid pool is a genuine second location, but the core role
  is nuclear HR. (Observation: the mitochondrion rows are ACCEPT although the reviewer describes them as non-core;
  left as is for consistency across the three rows, outside this batch's scope.)