ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene.[1]
Function
The function of the ERCC1 protein is predominantly in nucleotide excision repair (NER) of damaged DNA. NER is one of five separate DNA repair mechanisms that also include recombination repair, base excision repair, mismatch repair, and translesion synthesis.
Nucleotide excision repair in eukaryotes is initiated by either Global Genome NER(GG-NER) or Transcription Coupled NER(TC-NER) which involve distinct protein complexes, each recognizing damaged DNA. Thereafter, subsequent steps in GG-NER and TC-NER share a final common excision and repair pathway. Transcription factor II H (TFIIH) separates the abnormal strand from the normal strand. Xeroderma pigmentosum group G (XPG) cuts 3’ to the damaged DNA. Replication protein A (RPA) protects the normal strand. Xeroderma pigmentosum group A (XPA) isolates the damaged segment on the strand to be cut. ERCC1 and xeroderma pigmentosum group F (XPF) cut 5' to the damaged DNA. ERCC1 appears to have a crucial role in stabilizing and enhancing the functionality of the XPF endonuclease. The excised single-stranded DNA of approximately 30 nucleotides and attached NER proteins are removed. DNA polymerases and ligases fill in the gap using the normal strand as a template.
In mammals, the XPF/ERCC1 protein complex also removes nonhomologous 3′ tail ends in homologous recombination. ERCC1 has a role in homology-dependent gene targeting events. In telomere maintenance, XPF/ERCC1 degrades 3′ G-rich overhangs [2] and may have other functions. [3]
ERCC1 knockout mice are runted at birth and die from progressive hepatic insufficiency. Liver failure also occurs in XPF knockout mice, but not mice deficient in any other nucleotide excision repair protein.
Clinical significance
Mutations in the human ERCC1 gene result in cerebrooculofacioskeletal syndrome[4][5] and polymorphisms that alter expression of this gene may play a role in carcinogenesis.[6]
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. Nucleotide excision repair (NER) is the primary DNA repair mechanism that removes the therapeutic platinum-DNA adducts from the tumor DNA. ERCC1 activity levels, being an important part of the NER common final pathway, may serve as a marker of general NER throughput. This has been suggested for patients with gastric,[7] ovarian, colorectal and bladder cancers.[8] In Non-small cell lung carcinoma (NSCLC), surgically removed tumors that receive no further therapy have a better survival if ERCC1-positive than if ERCC1-negative. Thus ERCC1 positivity is a favorable prognostic marker, referring to how the disease will proceed if not further treated. ERCC1-positive NSCLC tumors do not benefit from adjuvant platinum chemotherapy. However, ERCC1-negative NSCLC tumors, prognostically worse without treatment, derive substantial benefit from adjuvant cisplatin-based chemotherapy. High ERCC1 is thus a negative predictive marker, referring to how it will respond to a specific type of treatment.[9][10]
ERCC1 genotyping in humans has shown significant polymorphism at codon 118. These polymorphisms may have differential effects on platinum and mitomycin damage.
References
- ^ Westerveld A, Hoeijmakers JH, van Duin M, de Wit J, Odijk H, Pastink A, Wood RD, Bootsma D (Sep 1984). "Molecular cloning of a human DNA repair gene". Nature 310 (5976): 425–9. doi:10.1038/310425a0. PMID 6462228.
- ^ Kirschner K, Melton DW (September 2010). "Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs". Anticancer Res. 30 (9): 3223–32. PMID 20944091.
- ^ Rahn JJ, Adair GM, Nairn RS (July 2010). "Multiple roles of ERCC1-XPF in mammalian interstrand crosslink repair". Environ. Mol. Mutagen. 51 (6): 567–81. doi:10.1002/em.20583. PMID 20658648.
- ^ Suzumura H, Arisaka O (2010). Cerebro-Oculo-Facio-Skeletal Syndrome. "Cerebro-oculo-facio-skeletal syndrome.". Adv Exp Med Biol. Advances in Experimental Medicine and Biology 685: 210–4. doi:10.1007/978-1-4419-6448-9_19. ISBN 978-1-4419-6447-2. PMID 20687508.
- ^ >Jaspers, N. G. J., Raams, A., Silengo, M. C., Wijgers, N., Niedernhofer, L. J., Robinson, A. R., Giglia-Mari, G., Hoogstraten, D., Kleijer, W. J., Hoeijmakers, J. H. J., Vermeulen, W. (2007). "First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure". Am. J. Hum. Genet. 80 (3): 457–466, 2007. doi:10.1086/512486. PMC 1821117. PMID 17273966. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1821117.
- ^ Goode EL, Ulrich CM, Potter JD (2002). "Polymorphisms in DNA repair genes and associations with cancer risk". Cancer Epidemiol Biomarkers Prev 11 (12): 1513–30. PMID 12496039.
- ^ Kwon HC, Roh MS, Oh SY, Kim SH, Kim MC, Kim JS et al. (2007). "Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer". Ann Oncol 18 (3): 504–9. doi:10.1093/annonc/mdl430. PMID 17322540.
- ^ Bellmunt J, Paz-Ares L, Cuello M, Cecere FL, Albiol S, Guillem V et al. (2007). "Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy". Ann Oncol 18 (3): 522–8. doi:10.1093/annonc/mdl435. PMID 17229776.
- ^ Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V et al. (2006). "DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy". N Engl J Med 355 (10): 983–91. doi:10.1056/NEJMoa060570. PMID 16957145.
- ^ Soria JC (2007). "ERCC1-tailored chemotherapy in lung cancer: the first prospective randomized trial". J Clin Oncol 25 (19): 2648–9. doi:10.1200/JCO.2007.11.3167. PMID 17602070.
Further reading
- Olaussen KA, Mountzios G, Soria JC (2007). "ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer". Current opinion in pulmonary medicine 13 (4): 284–9. doi:10.1097/MCP.0b013e32816b5c63. PMID 17534174.
- van Duin M, de Wit J, Odijk H, et al. (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. doi:10.1016/0092-8674(86)90014-0. PMID 2420469.
- van Duin M, van Den Tol J, Hoeijmakers JH, et al. (1989). "Conserved pattern of antisense overlapping transcription in the homologous human ERCC-1 and yeast RAD10 DNA repair gene regions". Mol. Cell. Biol. 9 (4): 1794–8. PMC 362600. PMID 2471070. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=362600.
- Hoeijmakers JH (1987). "Characterization of genes and proteins involved in excision repair of human cells". J. Cell Sci. Suppl. 6: 111–25. PMID 2821019.
- Hoeijmakers JH, van Duin M, Westerveld A, et al. (1987). "Identification of DNA repair genes in the human genome". Cold Spring Harb. Symp. Quant. Biol. 51 Pt 1: 91–101. PMID 3034490.
- van Duin M, van den Tol J, Warmerdam P, et al. (1988). "Evolution and mutagenesis of the mammalian excision repair gene ERCC-1". Nucleic Acids Res. 16 (12): 5305–22. doi:10.1093/nar/16.12.5305. PMC 336769. PMID 3290851. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=336769.
- Nagai A, Saijo M, Kuraoka I, et al. (1995). "Enhancement of damage-specific DNA binding of XPA by interaction with the ERCC1 DNA repair protein". Biochem. Biophys. Res. Commun. 211 (3): 960–6. doi:10.1006/bbrc.1995.1905. PMID 7598728.
- Li L, Elledge SJ, Peterson CA, et al. (1994). "Specific association between the human DNA repair proteins XPA and ERCC1". Proc. Natl. Acad. Sci. U.S.A. 91 (11): 5012–6. doi:10.1073/pnas.91.11.5012. PMC 43920. PMID 8197174. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=43920.
- Park CH, Sancar A (1994). "Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins". Proc. Natl. Acad. Sci. U.S.A. 91 (11): 5017–21. doi:10.1073/pnas.91.11.5017. PMC 43921. PMID 8197175. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=43921.
- McWhir J, Selfridge J, Harrison DJ, et al. (1994). "Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning". Nat. Genet. 5 (3): 217–24. doi:10.1038/ng1193-217. PMID 8275084.
- Trask B, Fertitta A, Christensen M, et al. (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. doi:10.1006/geno.1993.1021. PMID 8432525.
- Yu JJ, Mu C, Lee KB, et al. (1997). "A nucleotide polymorphism in ERCC1 in human ovarian cancer cell lines and tumor tissues". Mutat. Res. 382 (1–2): 13–20. PMID 9360634.
- Hayashi T, Takao M, Tanaka K, Yasui A (1998). "ERCC1 mutations in UV-sensitive Chinese hamster ovary (CHO) cell lines". Mutat. Res. 407 (3): 269–76. PMID 9653453.
- de Laat WL, Sijbers AM, Odijk H, et al. (1998). "Mapping of interaction domains between human repair proteins ERCC1 and XPF". Nucleic Acids Res. 26 (18): 4146–52. doi:10.1093/nar/26.18.4146. PMC 147836. PMID 9722633. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=147836.
- Lin YW, Kubota M, Koishi S, et al. (1998). "Analysis of mutations at the DNA repair genes in acute childhood leukaemia". Br. J. Haematol. 103 (2): 462–6. doi:10.1046/j.1365-2141.1998.00973.x. PMID 9827920.
- Houtsmuller AB, Rademakers S, Nigg AL, et al. (1999). "Action of DNA repair endonuclease ERCC1/XPF in living cells". Science 284 (5416): 958–61. doi:10.1126/science.284.5416.958. PMID 10320375.
- Cheng L, Guan Y, Li L, et al. (1999). "Expression in normal human tissues of five nucleotide excision repair genes measured simultaneously by multiplex reverse transcription-polymerase chain reaction". Cancer Epidemiol. Biomarkers Prev. 8 (9): 801–7. PMID 10498399.
- Yu JJ, Thornton K, Guo Y, et al. (2002). "An ERCC1 splicing variant involving the 5'-UTR of the mRNA may have a transcriptional modulatory function". Oncogene 20 (52): 7694–8. doi:10.1038/sj.onc.1204977. PMID 11753647.
- Li QQ, Yunmbam MK, Zhong X, et al. (2002). "Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC-1 expression". Cell. Mol. Biol. (Noisy-le-grand) 47 Online Pub: OL61–72. PMID 11936875.
External links
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PDB gallery
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1z00: Solution structure of the C-terminal domain of ERCC1 complexed with the C-terminal domain of XPF
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2a1i: Crystal Structure of the Central Domain of Human ERCC1
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2a1j: Crystal Structure of the Complex between the C-Terminal Domains of Human XPF and ERCC1
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| Excision repair |
Base excision repair/ AP site ( DNA glycosylase, Uracil-DNA glycosylase, Poly ADP ribose polymerase) • Nucleotide excision repair/ ERCC ( XPA, XPB, XPC, XPD/ERCC2, XPE/DDB1, XPF/DDB1, XPG/ERCC5, ERCC1, RPA, RAD23A, RAD23B, Excinuclease)
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| Other forms of repair |
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| Other/ungrouped proteins |
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| Regulation |
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| Other/ungrouped |
8-Oxoguanine • Adaptive response • Meiotic recombination checkpoint • RecF pathway
DNA helicase: BLM · WRN
FANC proteins: core protein complex ( FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM), FANCD1, FANCD2, FANCI, FANCJ, FANCN
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see also DNA repair-deficiency disorder
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
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