ERCC1

1Z00, 2A1I, 2A1J, 2JNW, 2JPD, 2MUT206713870ENSG00000012061ENSMUSG00000003549P07992P07903NM_001166049NM_001983NM_202001NM_001127324NM_007948NP_001356339NP_001356340NP_001356341NP_001356342NP_001356343NP_001356344NP_001356345NP_001356346NP_001356347NP_001356348NP_001120796NP_031974DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 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 XPF2a1i: Crystal Structure of the Central Domain of Human ERCC12a1j: Crystal Structure of the Complex between the C-Terminal Domains of Human XPF and ERCC1 DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination. 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 ERCC1 are more sensitive than normal to particular DNA damaging agents, including ultraviolet (UV) radiation and to chemicals that cause crosslinking between DNA strands. Genetically engineered mice with disabling mutations in ERCC1 have defects in DNA repair, accompanied by metabolic stress-induced changes in physiology that result in premature aging. Complete deletion of ERCC1 is incompatible with viability of mice, and no human individuals have been found with complete (homozygous) deletion of ERCC1. Rare individuals in the human population harbor inherited mutations that impair the function of ERCC1. When the normal genes are absent, these mutations can lead to human syndromes, including Cockayne syndrome (CS) and COFS. ERCC1 and ERCC4 are the gene names assigned in mammalian genomes, including the human genome (Homo sapiens). Similar genes with similar functions are found in all eukaryotic organisms. The genomic DNA for ERCC1 was the first human DNA repair gene to be isolated by molecular cloning. The original method was by transfer of fragments of the human genome to ultraviolet light (UV)-sensitive mutant cell lines derived from Chinese hamster ovary cells. Reflecting this cross-species genetic complementation method, the gene was called “Excision repair cross-complementing 1”. Multiple independent complementation groups of Chinese hamster ovary (CHO) cells were isolated, and this gene restored UV resistance to cells of complementation group 1. The human ERCC1 gene encodes the ERCC1 protein of 297 amino acids with a molecular mass of about 32,500 daltons. Genes similar to ERCC1 with equivalent functions (orthologs) are found in other eukaryotic genomes. Some of the most studied gene orthologs include RAD10 in the budding yeast Saccharomyces cerevisiae, and swi10+ 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 domains separated by a less conserved region in the middle. The N-terminal region 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. Most of the ERCC1 protein is related at the sequence level to the C-terminus of the XPF protein, but residues in the nuclease domain are not present. A DNA binding “helix-hairpin-helix” domain at the C-terminus of each protein.