ERCC1
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DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene.[5] Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.[6][7]
Many aspects of these two
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.[8] 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.
Gene
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
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.
Protein
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.[9]
The ERCC4/XPF protein consists of two conserved domains separated by a less conserved region in the middle. The
By primary sequence and protein structural similarity, the ERCC1-XPF nuclease is a member of a broader family of structure specific DNA nucleases comprising two subunits. Such nucleases include, for example, the MUS81-EME1 nuclease.
Structure-specific nuclease
The ERCC1–XPF complex is a structure-specific endonuclease. ERCC1-XPF does not cut DNA that is exclusively single-stranded or double-stranded, but it cleaves the DNA phosphodiester backbone specifically at junctions between double-stranded and single-stranded DNA. It introduces a cut in double-stranded DNA on the 5′ side of such a junction, about two nucleotides away.[14] This structure-specificity was initially demonstrated for RAD10-RAD1, the yeast orthologs of ERCC1 and XPF.[15]
The hydrophobic helix–hairpin–helix motifs in the C-terminal regions of ERCC1 and XPF interact to promote dimerization of the two proteins.[16] There is no catalytic activity in the absence of dimerization. Indeed, although the catalytic domain is within XPF and ERCC1 is catalytically inactive, ERCC1 is indispensable for activity of the complex.
Several models have been proposed for binding of ERCC1–XPF to DNA, based on partial structures of relevant protein fragments at atomic resolution.[16] DNA binding mediated by the helix-hairpin-helix domains of ERCC1 and XPF domains positions the heterodimer at the junction between double-stranded and single-stranded DNA.
Nucleotide excision repair
During nucleotide excision repair, several protein complexes cooperate to recognize damaged DNA and locally separate the DNA helix for a short distance on either side of the site of a DNA damage. The ERCC1–XPF nuclease incises the damaged DNA strand on the 5′ side of the lesion.[14] During NER, the ERCC1 protein interacts with the XPA protein to coordinate DNA and protein binding.
DNA double-strand break repair
Mammalian cells with mutant ERCC1–XPF are moderately more sensitive than normal cells to agents (such as ionizing radiation) that cause double-stranded breaks in DNA.[17][18] Particular pathways of both homologous recombination repair and non-homologous end-joining rely on ERCC1-XPF function.[19][20] 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. This activity is needed during a single-strand annealing subpathway of homologous recombination. Trimming of 3’ single-stranded tail is also needed in a mechanistically distinct subpathway of non-homologous end-joining, dependent on the Ku proteins.[17] Homologous integration of DNA, an important technique for genetic manipulation, is dependent on the function of ERCC1-XPF in the host cell.[21]
DNA interstrand crosslink repair
Mammalian cells carrying mutations in ERCC1 or XPF are especially sensitive to agents that cause DNA interstrand crosslinks.[22] Interstrand crosslinks block the progression of DNA replication, and structures at blocked DNA replication forks provide substrates for cleavage by ERCC1-XPF.[23][24] Incisions may be made on either side of the crosslink on one DNA strand to unhook the crosslink and initiate repair. Alternatively, a double-strand break may be made in the DNA near the ICL, and subsequent homologous recombination repair may involve ERCC1-XPF action. Although not the only nuclease involved, ERCC1–XPF is required for ICL repair during several phases of the cell cycle.[25][26]
Clinical significance
Cerebro-oculo-facio-skeletal syndrome
A few patients with severely disabling ERCC1 mutations that cause
Cockayne syndrome
One Cockayne syndrome (CS) type II patient designated CS20LO exhibited a homozygous mutation in exon 7 of ERCC1, producing a F231L mutation.[29]
Relevance in chemotherapy
Measuring ERCC1 activity may have utility in clinical cancer medicine because one mechanism of resistance to platinum chemotherapy drugs correlates with high ERCC1 activity.
Deficiency in cancer
ERCC1 protein expression is reduced or absent in 84% to 100% of
Cadmium (Cd) and its compounds are well-known human carcinogens. During Cd-induced malignant transformation, the promoter regions of ERCC1, as well as of hMSH2, XRCC1, and hOGG1, were heavily methylated and both the messenger RNA and proteins of these DNA repair genes were progressively reduced.[40] DNA damage also increased with Cd-induced transformation.[40] Reduction of protein expression of ERCC1 in progression to sporadic cancer is unlikely to be due to mutation. While germ line (familial) mutations in DNA repair genes cause a high risk of cancer (see inherited impairment in DNA repair increases cancer risk), somatic mutations in DNA repair genes, including ERCC1, only occur at low levels in sporadic (non-familial) cancers.[41]
Control of ERCC1 protein level occurred at the translational level. In addition to the wild-type sequence, three
Repression of let-7a can cause repression of ERCC1 expression through an intermediary step involving the HMGA2 gene. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present.[45] (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are chromatin architectural transcription factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing local DNA conformation. Regulation is achieved by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors.[46] HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression.[47] Hypermethylation of the promoter for let-7a miRNA reduces its expression and this allows hyperexpression of HMGA2. Hyperexpression of HMGA2 can then reduce expression of ERCC1.
Thus, there are three mechanisms that may be responsible for the low level of protein expression of ERCC1 in 84% to 100% of sporadic colon cancers. From results in gliomas and in cadmium carcinogenesis, methylation of the ERCC1 promoter may be a factor. One or more miRNAs that repress ERCC1 may be a factor. And epigenetically reduced let-7a miRNA allowing hyperexpression of HMGA2 could also reduce protein expression of ERCC1 in colon cancers. Which epigenetic mechanism occurs most frequently, or whether multiple epigenetic mechanisms reduce ERCC1 protein expression in colon cancers has not been determined.[citation needed]
Accelerated aging
DNA repair-deficient Ercc1 mutant mice show numerous features of accelerated aging, and have a limited lifespan.[48] Accelerated aging in the mutant involves various organs. Ercc1 mutant mice are deficient in several DNA repair processes including transcription-coupled DNA repair. This deficiency prevents resumption of RNA synthesis on the template DNA strand subsequent to it receiving a transcription-blocking DNA damage. Such blockages of transcription appear to promote premature aging, particularly in non-proliferating or slowly proliferating organs such as the nervous system, liver and kidney[49] (see DNA damage theory of aging).
When Ercc1 mutant mice were subjected to dietary restriction their response closely resembled the beneficial response to dietary restriction of wild-type mice. Dietary restriction extended the lifespan of the Ercc1 mutant mice from 10 to 35 weeks for males and from 13 to 39 weeks for females.[48] It appears that in Ercc1 mutant mice dietary restriction while delaying aging also attenuates accumulation of genome-wide DNA damage and preserves transcriptional output, likely contributing to improved cell viability.[48]
Spermatogenesis and oogenesis
Both male and female Ercc1-deficient mice are infertile.[50] The DNA repair function of Ercc1 appears to be required in both male and female germ cells at all stages of their maturation. The testes of Ercc1-deficient mice have an increased level of 8-oxoguanine in their DNA, suggesting that Ercc1 may have a role in removing oxidative DNA damages.
Notes
Wikidata Q35663361 . |
References
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Further reading
- Olaussen KA, Mountzios G, Soria JC (July 2007). "ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer". Current Opinion in Pulmonary Medicine. 13 (4): 284–9. S2CID 23038328.
- van Duin M, de Wit J, Odijk H, Westerveld A, Yasui A, Koken MH, et al. (March 1986). "Molecular characterization of the human excision repair gene ERCC-1: cDNA cloning and amino acid homology with the yeast DNA repair gene RAD10". Cell. 44 (6): 913–23. S2CID 40370483.
- van Duin M, van Den Tol J, Hoeijmakers JH, Bootsma D, Rupp IP, Reynolds P, et al. (April 1989). "Conserved pattern of antisense overlapping transcription in the homologous human ERCC-1 and yeast RAD10 DNA repair gene regions". Molecular and Cellular Biology. 9 (4): 1794–8. PMID 2471070.
- Hoeijmakers JH (1987). "Characterization of genes and proteins involved in excision repair of human cells". Journal of Cell Science. Supplement. 6: 111–25. PMID 2821019.
- Hoeijmakers JH, van Duin M, Westerveld A, Yasui A, Bootsma D (1987). "Identification of DNA repair genes in the human genome". Cold Spring Harbor Symposia on Quantitative Biology. 51 Pt 1 (1): 91–101. PMID 3034490.
- van Duin M, van den Tol J, Warmerdam P, Odijk H, Meijer D, Westerveld A, et al. (June 1988). "Evolution and mutagenesis of the mammalian excision repair gene ERCC-1". Nucleic Acids Research. 16 (12): 5305–22. PMID 3290851.
- Nagai A, Saijo M, Kuraoka I, Matsuda T, Kodo N, Nakatsu Y, et al. (June 1995). "Enhancement of damage-specific DNA binding of XPA by interaction with the ERCC1 DNA repair protein". Biochemical and Biophysical Research Communications. 211 (3): 960–6. PMID 7598728.
- Li L, Elledge SJ, Peterson CA, Bales ES, Legerski RJ (May 1994). "Specific association between the human DNA repair proteins XPA and ERCC1". Proceedings of the National Academy of Sciences of the United States of America. 91 (11): 5012–6. PMID 8197174.
- Park CH, Sancar A (May 1994). "Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins". Proceedings of the National Academy of Sciences of the United States of America. 91 (11): 5017–21. PMID 8197175.
- McWhir J, Selfridge J, Harrison DJ, Squires S, Melton DW (November 1993). "Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning". Nature Genetics. 5 (3): 217–24. S2CID 20715351.
- Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A, et al. (January 1993). "Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers". Genomics. 15 (1): 133–45. PMID 8432525.
- Yu JJ, Mu C, Lee KB, Okamoto A, Reed EL, Bostick-Bruton F, et al. (September 1997). "A nucleotide polymorphism in ERCC1 in human ovarian cancer cell lines and tumor tissues". Mutation Research. 382 (1–2): 13–20. PMID 9360634.
- Hayashi T, Takao M, Tanaka K, Yasui A (June 1998). "ERCC1 mutations in UV-sensitive Chinese hamster ovary (CHO) cell lines". Mutation Research. 407 (3): 269–76. PMID 9653453.
- de Laat WL, Sijbers AM, Odijk H, Jaspers NG, Hoeijmakers JH (September 1998). "Mapping of interaction domains between human repair proteins ERCC1 and XPF". Nucleic Acids Research. 26 (18): 4146–52. PMID 9722633.
- Lin YW, Kubota M, Koishi S, Sawada M, Usami I, Watanabe K, Akiyama Y (November 1998). "Analysis of mutations at the DNA repair genes in acute childhood leukaemia". British Journal of Haematology. 103 (2): 462–6. S2CID 25175169.
- Houtsmuller AB, Rademakers S, Nigg AL, Hoogstraten D, Hoeijmakers JH, Vermeulen W (May 1999). "Action of DNA repair endonuclease ERCC1/XPF in living cells". Science. 284 (5416): 958–61. PMID 10320375.
- Cheng L, Guan Y, Li L, Legerski RJ, Einspahr J, Bangert J, et al. (September 1999). "Expression in normal human tissues of five nucleotide excision repair genes measured simultaneously by multiplex reverse transcription-polymerase chain reaction". Cancer Epidemiology, Biomarkers & Prevention. 8 (9): 801–7. PMID 10498399.
- Yu JJ, Thornton K, Guo Y, Kotz H, Reed E (November 2001). "An ERCC1 splicing variant involving the 5'-UTR of the mRNA may have a transcriptional modulatory function". Oncogene. 20 (52): 7694–8. PMID 11753647.
- Li QQ, Yunmbam MK, Zhong X, Yu JJ, Mimnaugh EG, Neckers L, Reed E (2002). "Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC-1 expression". Cellular and Molecular Biology. 47 Online Pub: OL61-72. PMID 11936875.