XRCC3 (human, O43542) curation notes

Provenance / process

• 2026-10-06: New review triggered by PMID:42682019 (Dwivedi et al., Biochem Soc Trans 2026,
  "Distinct functions of mammalian RAD51 paralogs in genome maintenance"), reviewed together with
  targeted updates to the RAD51C and XRCC2 reviews.
• just deep-research-falcon human XRCC3 --fallback perplexity-lite failed (no provider available
  in this environment), so there is no -deep-research-*.md file. Research below is from the
  cached primary literature in publications/.

Key findings (with provenance)

Complexes

• CX3 = RAD51C-XRCC3, purified from human cells PMID:11751635.
• New assemblies (2026 cryo-EM, three independent groups):
• X3CDX2 (XRCC3-RAD51C-RAD51D-XRCC2) caps the 5' end of RAD51 filaments
  PMID:41196948;
  XRCC3 contacts RAD51 and XRCC2 forms the cap PMID:41196948.
• BCDX2-CX3-RAD51 "loader" and DX2-CX3 "anchor" PMID:41772053.
• Autoinhibited RAD51-X3C octamer, remodeled by DX2 into RAD51-X3CDX2 PMID:42020761.
• There is no GO cellular-component term for X3CDX2; only GO:0033065 (Rad51C-XRCC3 complex)
  and GO:0033063 (BCDX2) exist. Raised as a suggested question rather than a knowledge gap
  (ontology gap, not biology).

Molecular activity

• XRCC3-containing complexes stimulate RAD51 strand exchange / D-loop formation:
• PMID:41196948
• PMID:41772053
• PMID:42020761
• XRCC3's own RAD51-contacting loop is required PMID:42020761.
• -> NEW contributes_to GO:0140619 DNA strand exchange activator activity. Comparator check:
  RAD51AP1 carries GO:0140619 (IDA) for the same kind of RAD51 stimulation; absence on XRCC3
  reflects the 2026 publication date.
• Holliday junction and fork junction binding by CX3 PMID:20207730.

HR

• CX3 acts downstream of RAD51 recruitment PMID:23149936.
• Late-stage HR roles: altered gene-conversion tracts PMID:12191483; reduced HJ resolvase
  activity in mutant extracts PMID:14716019; XRCC3 with GEN1 at HJ resolution PMID:23108668.
  The resolvase catalysis is GEN1's: crossover-junction endonuclease MF annotations to XRCC3 are
  marked over-annotated (consistent with RAD51C review).

Replication stress

• XRCC3 at nascent DNA of stalled forks; RAD51C/XRCC3 ATP hydrolysis needed for restart; XRCC2
  dispensable for restart PMID:26354865.
• XRCC3 S225 phosphorylation (ATR, in ATM pathway; requires RAD51C not XRCC2) needed for RAD51
  chromatin loading, HR, and collapsed (not stalled) fork recovery PMID:23438602.
• Purified CX3: no fork reversal; modest fork protection vs BCDX2 PMID:37843130.
• Trigger review: "only the CX3 complex participates in restarting stalled/collapsed replication
  forks" PMID:42682019. Note the review also says FBH1-remodeled forks are protected by DX2 and
  CX3 (its ref 97); the primary paper was not identified/cached, so not used.

R-loops

• CX3 binds FANCM and recruits it to R-loops; independent of fork functions; XRCC3 S225A
  complements PMID:41719405. -> NEW GO:0062176 R-loop processing (non-core; single study).
  Comparator check: GO:0062176 in human is carried by non-catalytic recruiters/regulators
  (SIRT7, SRPK2, NFAT5) as well as nucleases (MRE11).
  QuickGO query (2026-10-10; goId=GO:0062176, goUsage=exact, taxonId=9606) returns 10 rows, all
  involved_in IDA assigned by UniProt: SIRT7 (Q9NRC8, PMID:28790157; deacetylase of the helicase
  DDX21), SRPK2 (P78362, PMID:28076779; kinase acting on the helicase DDX23), NFAT5 (O94916,
  PMID:34049076), MRE11/RAD50/NBN (PMID:31537797), PRIMPOL (PMID:30478192), DDX21 (PMID:28790157),
  DDX23 (PMID:28076779), RAD54L2 (PMID:39028815). So regulators that act on the resolving enzyme,
  not only the enzymes themselves, carry the term, which is the role CX3 plays for FANCM.

Mitochondria

• XRCC3 in mitochondria PMID:20413593; RAD51C/XRCC3 in mitochondrial nucleoid, supports mtDNA
  synthesis and POLG retention PMID:29158291. -> NEW located_in GO:0042645 mitochondrial
  nucleoid. No process NEW proposed (mtDNA replication) - the evidence is necessity/support of
  POLG, and RAD51C review did not add one either.

Telomeres

• XRCC3-dependent t-loop HR deletion PMID:15507207, telomere trimming [PMID:21903669,
  PMID:27918544]. Kept as non-core.

Mitotic phenotypes

• Centrosome / SAC phenotypes after XRCC3 loss PMID:23108668 are attributed to unresolved DNA
  damage PMID:11025669;
  annotations to centrosome duplication / SAC regulation marked over-annotated (not removed, full
  text not available).

Decisions summary

• 13 GO:0005515 protein binding IPIs -> REMOVE (uninformative; interactions captured by CX3 complex
  CC and the strand-exchange-activator MF).
• GO:0140664 ATP-dependent DNA damage sensor activity (InterPro2GO) -> MARK_AS_OVER_ANNOTATED, as for
  RAD51C and XRCC2.
• GO:0000730 DNA recombinase assembly considered for core function 1 but omitted: the trigger
  review notes X3CDX2 "is unable to stimulate RAD51 filament formation on RPA-coated ssDNA", while
  PMID:42020761 reports enhanced filament assembly; conflicting, so not asserted.

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

• GO:0062176 comparator substantiated with the QuickGO query and evidence codes (above).
• Completed the truncated PMID:41196948 quote.
• GO:0000403 Y-form DNA binding considered and not added: the PMID:20207730 fork substrate has duplex
  arms, and the authors conclude ssDNA does not drive recognition, whereas GO:0000403 is defined by
  unpaired strands at one end.