ERCC4 (XPF) — gene review notes

UniProt: Q92889 (XPF_HUMAN); HGNC:3436; Gene: ERCC4 (syn. ERCC11, XPF, FANCQ). 916 aa.
EC=3.1.-.- (Mg2+ dependent hydrolase/endonuclease).

Core biology (verified against cached publications)

XPF/ERCC4 is the catalytic subunit of the ERCC1-XPF structure-specific DNA
endonuclease. It houses the nuclease active site and makes the 5' incision on the
damaged strand at ss/ds DNA junctions. ERCC1 is the non-catalytic partner that provides
additional DNA binding.

• UniProt FUNCTION: "Catalytic component of a structure-specific DNA repair endonuclease
  responsible for the 5-prime incision during DNA repair, and which is essential for
  nucleotide excision repair (NER) and interstrand cross-link (ICL) repair."
• Cofactor: Mg(2+) PMID:10413517.
• Heterodimer with ERCC1; C-terminal (HhH)2 domain mediates dimerization; N-terminal
  nuclease/helicase-like region carries the catalytic domain.

Endonuclease / catalytic subunit

• PMID:8797827
• PMID:8797827
• PMID:10413517
• PMID:10413517
• PMID:10413517
• PMID:22547097
• PMID:22547097
• PMID:16076955

ssDNA binding / substrate recognition (ss/ds junction)

• PMID:22483113
• PMID:22483113
• PMID:16076955 (ERCC1 side)
• ssDNA binding by XPF: PMID:10413517 (binds DNA in absence of ERCC1).

NER

• PMID:8797827
• PMID:22547097
• PMID:17055345

Interstrand crosslink (ICL) repair — 5' and 3' unhooking incisions

• PMID:11790111
• PMID:14728600
• PMID:16678501
• PMID:32034146
• FANCA/spectrin recruitment to ICL foci: PMID:12571280

Homologous recombination / single-strand annealing (SSA)

• PMID:14734547
• PMID:14734547
• Meiotic recombination (phylogenetic, yeast Rad1/Rad16/Mei-9): PMID:10644440

SLX4 (FANCP) coordination

• PMID:19596235
• PMID:24012755 and maps SLX4 interactions with SLX1, XPF, MUS81.
• Also PMID:19596236, PMID:19595721, PMID:19595722 (SLX4/BTBD12 binds XPF-ERCC1).

Telomere functions (3' overhang removal; specialized/non-core)

• PMID:14690602
• PMID:14690602 and represses Telomeric DNA-containing Double Minute chromosomes (TDMs).
• PMID:18812185
• PMID:18812185 shows two distinct mechanisms: TRF2 control (nuclease-dependent) vs telomere-length modulation (nuclease-independent). Establishes the NOT annotation for telomerase inhibitor activity — XPF does NOT act as a telomerase inhibitor.
• PMID:17055345

Regulation / PTM

• Acetylation at Lys911 by KAT5/TIP60 promotes XPF-ERCC1 assembly by disrupting the
  Glu907-Lys911 salt bridge, exposing a second ERCC1 binding site; deacetylated by SIRT1
  PMID:32034146.

Disease (all reflect the same endonuclease deficiency)

• Xeroderma pigmentosum group F (XP-F, MIM:278760)
• XFE progeroid syndrome (XFEPS, MIM:610965) — R153P PMID:17183314
• XPF/Cockayne syndrome (XPF/CS) PMID:23623389
• Fanconi anemia complementation group Q (FANCQ, MIM:615272) — L230P, R689S, S786F
  [PMID:23623386, PMID:24027083]

Curation decisions summary

• Core MF = structure-specific 5' incision endonuclease (ss/ds junction); catalytic subunit.
  Best specific MF ids: GO:0000014 (single-stranded DNA endodeoxyribonuclease activity),
  GO:1990599 (3' overhang ssDNA endonuclease activity, telomere).
• All GO:0005515 "protein binding" (and GO:0042802 identical protein binding) → MARK_AS_OVER_ANNOTATED
  (uninformative; functional partners ERCC1/SLX4/RAD52/TRF2/FANCA captured elsewhere).
• Telomere / recombination / meiotic / NHEJ processes → KEEP_AS_NON_CORE (genuine but specialized).
• Negated GO:0010521 telomerase inhibitor activity → ACCEPT the negation (informative NOT).
• No REMOVE and no UNDECIDED: all key claims verifiable in cached abstracts.