ERCC4 - dismech genes

Normal function · from ai-gene-review (Q92889, commit 79fe13b38970) · AI-generated, not KB evidence

ERCC4/XPF is the catalytic subunit of the ERCC1-XPF structure-specific DNA endonuclease, a Mg2+-dependent nuclease that cleaves DNA at single-stranded/ double-stranded junctions and makes the incision 5' to a lesion on the damaged strand. XPF houses the nuclease active site (N-terminal helicase-like/nuclease region), while its obligate partner ERCC1 (bound through the C-terminal double helix-hairpin-helix domain) contributes additional DNA binding but is catalytically inert. As the enzyme that makes the 5' incision, ERCC1-XPF is essential for nucleotide excision repair (NER), where it is recruited to lesions via XPA and, together with the 3'-incising ERCC5/XPG nuclease, excises the damage-containing oligonucleotide. The same structure-specific endonuclease performs the unhooking incisions that release DNA interstrand crosslinks (ICLs), where it is coordinated by SLX4/FANCP, and it processes recombination intermediates in homology-directed pathways including single-strand annealing (acting on 3' non-homologous flaps, stimulated by RAD52). ERCC1-XPF also acts at telomeres, removing the 3' single-stranded overhang from uncapped telomeres and negatively regulating telomere length. The enzyme localizes to the nucleus and to chromatin sites of DNA damage. Loss of XPF function underlies a spectrum of human disease that all reflects the same endonuclease deficiency - xeroderma pigmentosum group F, XPF-Cockayne syndrome, XFE progeroid syndrome, and Fanconi anemia complementation group Q.

Catalytic subunit of the ERCC1-XPF structure-specific endonuclease that makes the 5' incision on the damaged strand at single-stranded/double-stranded DNA junctions, the incision step required for nucleotide excision repair and for the unhooking of DNA interstrand crosslinks. XPF provides the Mg2+-dependent nuclease active site and the ssDNA-junction recognition, while its obligate partner ERCC1 provides additional DNA binding.

molecular function: single-stranded DNA endodeoxyribonuclease activity · directly involved in: nucleotide-excision repair; nucleotide-excision repair involved in interstrand cross-link repair · locations: nucleoplasm · in complex: ERCC4-ERCC1 complex

The same ERCC1-XPF structure-specific endonuclease cleaves non-homologous 3' flaps and 3' single-stranded overhangs, processing recombination intermediates during homology-directed double-strand break repair, most notably single-strand annealing where the activity is stimulated by RAD52. The identical 3'-overhang endonuclease activity also removes the 3' overhang from uncapped telomeres.

molecular function: 3' overhang single-stranded DNA endonuclease activity · directly involved in: double-strand break repair via homologous recombination · locations: nucleoplasm · in complex: ERCC4-ERCC1 complex

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Xeroderma Pigmentosum	causative germline	mechanism: Impaired nucleotide-excision repair subtype: XP-F scoped to subtype: XP-F
XFE Progeroid Syndrome	causative partial loss of function	mechanism: Biallelic Hypomorphic ERCC4 Variants
Fanconi_Anemia	untyped Pathogenic Variants	mechanism: Downstream Effector Dysfunction subtype: FA-Q

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
xeroderma pigmentosum group F MONDO:0010215	AR	Definitive 2019-08-14	Xeroderma Pigmentosum causative

Mechanism modules · computed from kb/

nucleotide_excision_repair_deficiency via Xeroderma Pigmentosum named in the module itself