ERCC4

1Z00, 2A1J, 2MUT, 2KN7, 2AQ0207250505ENSG00000175595ENSMUSG00000022545Q92889Q9QZD4NM_005236NM_015769NP_005227NP_056584ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene.

The ERCC1-XPF nuclease is an essential activity in the pathway of DNA nucleotide excision repair (NER).

Genetically engineered mice with disabling mutations in ERCC4 also have defects in DNA repair, accompanied by metabolic stress-induced changes in physiology that result in premature aging.

XPF provides the endonuclease active site and is involved in DNA binding and additional protein–protein interactions.

Most of the ERCC1 protein is related at the sequence level to the C terminus of the XPF protein.,[13] but residues in the nuclease domain are not present.

Several models have been proposed for binding of ERCC1–XPF to DNA, based on partial structures of relevant protein fragments at atomic resolution.

[20][21] The relevant activity of ERCC1–XPF for both types of double-strand break repair is the ability to remove non-homologous 3′ single-stranded tails from DNA ends before rejoining.

Trimming of 3’ single-stranded tails is also needed in a mechanistically distinct subpathway of non-homologous end-joining, independent of the Ku proteins[22][19] Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell.

Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair my involve ERCC1-XPF action.

Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle.

[29] These patients have characteristics of XP and CS, as well as additional neurologic, hepatobiliary, musculoskeletal and hematopoietic symptoms.

Several human patients with symptoms of Fanconi anemia (FA) have causative mutations in the ERCC4 gene.

FA patients with ERCC4 mutations have been classified as belonging to Fanconi anemia complementation group Q (FANCQ).

[28][30] ERCC4 (XPF) is normally expressed at a high level in cell nuclei within the inner surface of the colon (see image, panel C).

This is indicated by the brown color seen by immunostaining of ERCC4 (XPF) in almost all the cells in the crypt in panel C of the image in this section.

The tissue section in the image shown here was also counterstained with hematoxylin to stain DNA in nuclei a blue-gray color.

As indicated by Harper and Elledge,[33] defects in the ability to properly respond to and repair DNA damage underlie many forms of cancer.

Figure 1: Diagram of XPF showing an inactive helicase domain, a nuclease domain and a helix-hairpin-helix domain
Figure 2: DNA substrates of ERCC1-XPF nuclease
Sequential sections of the same colon crypt with immunohistochemical staining (brown) showing normal high expression of DNA repair proteins PMS2 (A), ERCC1 (B) and ERCC4 (XPF) (C). This crypt is from the biopsy of a 58-year-old male patient who never had colonic neoplasia and the crypt has high expression of these DNA repair proteins in absorptive cell nuclei throughout most of the crypt. Note that PMS2 and ERCC4 (XPF) expression (in panels A and C) are each reduced or absent in the nuclei of cells at the top of the crypt and within the surface of the colonic lumen between crypts. Original image, also in a publication. [ 31 ]
Sequential sections of a segment of colon epithelium near a colorectal cancer showing reduced or absent expression of PMS2 (A), ERCC1 (B) and ERCC4 (C) in the colon crypts. This tissue segment is from a histologically normal area of a colon resection of a male patient who had an adenocarcinoma in the sigmoid colon. For PMS2 (A), there is absent expression in cell nuclei of the crypt body, the crypt neck and the colonic lumen surface for all epithelial cells. For ERCC1 (B), there is reduced expression in most of the cell nuclei of the crypts, but there is high expression in cell nuclei at the neck of the crypts and in the adjacent colonic lumen surface. For ERCC4 (XPF) (C), there is absent expression in most of the cell nuclei of the crypts and in the colonic lumen in this area of tissue, but detectable expression at the neck of some crypts. The reductions or absence of expression of these DNA repair genes in this tissue appears to be due to epigenetic repression . [ 31 ] Original image, also in a publication. [ 31 ]