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.