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. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.1z00: Solution structure of the C-terminal domain of ERCC1 complexed with the C-terminal domain of XPF2a1j: Crystal Structure of the Complex between the C-Terminal Domains of Human XPF and ERCC12aq0: Solution structure of the human homodimeric dna repair protein XPF ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination. The nuclease enzyme ERCC1-XPF cuts specific structures of DNA. Many aspects of these two gene products are described together here because they are partners during DNA repair. The ERCC1-XPF nuclease is an essential activity in the pathway of DNA nucleotide excision repair (NER). The ERCC1-XPF nuclease also functions in pathways to repair double-strand breaks in DNA, and in the repair of 'crosslink' damage that harmfully links the two DNA strands. Cells with disabling mutations in ERCC4 are more sensitive than normal to particular DNA damaging agents, including ultraviolet radiation and to chemicals that cause crosslinking between DNA strands. 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. Complete deletion of ERCC4 is incompatible with viability of mice, and no human individuals have been found with complete (homozygous) deletion of ERCC4. Rare individuals in the human population harbor inherited mutations that impair the function of ERCC4. When the normal genes are absent, these mutations can lead to human syndromes, including xeroderma pigmentosum, Cockayne syndrome and Fanconi anemia. ERCC1 and ERCC4 are the human gene names and Ercc1 and Ercc4 are the analogous mammalian gene names. Similar genes with similar functions are found in all eukaryotic organisms. The human ERCC4 gene can correct the DNA repair defect in specific ultraviolet light (UV)-sensitive mutant cell lines derived from Chinese hamster ovary cells. Multiple independent complementation groups of Chinese hamster ovary (CHO) cells have been isolated, and this gene restored UV resistance to cells of complementation group 4. Reflecting this cross-species genetic complementation method, the gene was called 'Excision repair cross-complementing 4' The human ERCC4 gene encodes the XPF protein of 916 amino acids with a molecular mass of about 104,000 daltons. Genes similar to ERCC4 with equivalent functions (orthologs) are found in other eukaryotic genomes. Some of the most studied gene orthologs include RAD1 in the budding yeast Saccharomyces cerevisiae, and rad16+ in the fission yeast Schizosaccharomyces pombe. One ERCC1 molecule and one XPF molecule bind together, forming an ERCC1-XPF heterodimer which is the active nuclease form of the enzyme. In the ERCC1–XPF heterodimer, ERCC1 mediates DNA– and protein–protein interactions. XPF provides the endonuclease active site and is involved in DNA binding and additional protein–protein interactions. The ERCC4/XPF protein consists of two conserved areas separated by a less conserved region in the middle. The N-terminal area has homology to several conserved domains of DNA helicases belonging to superfamily II, although XPF is not a DNA helicase. The C-terminal region of XPF includes the active site residues for nuclease activity. (Figure 1).