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ERCC2  -  excision repair cross-complementation group 2

Homo sapiens

Synonyms: BTF2 p80, Basic transcription factor 2 80 kDa subunit, COFS2, CXPD, DNA excision repair protein ERCC-2, ...
 
 
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Disease relevance of ERCC2

  • Two of them, ERCC2 and ERCC3, are responsible for atypical forms of XP disorders which confer a high predisposition to skin cancer [1].
  • To narrow the location of this tumor suppressor further, we studied 138 gliomas for loss of allelic heterozygosity at six microsatellite polymorphisms between APOC2 and HRC, including a newly described polymorphism in the ERCC2 gene [2].
  • On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T>C, Asp(568)Asp), ERCC2 (G>A, Asp(711)Asp), CYP2D6*4 (G>A, splicing defect), mean bladder dose >60 Gy, and dose to 30% of rectal volume >75 Gy [3].
  • Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype [4].
  • In this review, the authors focused on the x-ray repair cross-complementing protein group 3 (XRCC3) and xeroderma pigmentosum group D (XPD)/excision repair cross-complementing rodent repair deficiency (ERCC2) genes, because they are among the most extensively studied but no final conclusion has yet been drawn about their role in cancer occurrence [5].
 

Psychiatry related information on ERCC2

  • The p44 subunit plays a crucial role in the overall activity of the transcription/DNA repair factor TFIIH: on the one hand its N-terminal domain interacts with and regulates the XPD helicase (, ); on the other hand, as shown in the present study, it participates with the promoter escape reaction [6].
  • The influence of the XPA-A23A genotype was not evident in this statistical analysis, and no associations with XPD polymorphisms, dietary habits or tobacco smoking were found [7].
  • Besides XP, mutations in XPD can cause another seemingly unrelated syndrome, trichothiodystrophy (TTD), characterized by sulfur-deficient brittle hair, ichthyosis, and physical and mental retardation [8].
  • The mean TTD was 13.8 +/- 10.8 months and did not differ by gender, household composition, or type of dementia [9].
  • The brothers were divided into more (MAG) and less active groups according to physical activity and fitness [10].
 

High impact information on ERCC2

  • DNA repair-deficient trichothiodystrophy (TTD) results from mutations in the XPD and XPB subunits of the DNA repair and transcription factor TFIIH [11].
  • We demonstrate that the XPD mutation alters cdk7 function in RARalpha phosphorylation [12].
  • Inherited mutations in the XPD subunit of the general transcription/repair factor TFIIH yield the rare genetic disorder Xeroderma pigmentosum (XP), the phenotypes of which cannot be explained solely on the basis of a DNA repair defect [12].
  • XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha [12].
  • Transactivation is restored upon overexpression of either the wild-type XPD or the RARalphaS77E (a mutation which mimics phosphorylated RARalpha) [12].
 

Chemical compound and disease context of ERCC2

 

Biological context of ERCC2

  • The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor [1].
  • A long-range restriction map of the human chromosome 19q13 region: close physical linkage between CKMM and the ERCC1 and ERCC2 genes [17].
  • We demonstrated previously that DRC for removal of benzo[a]pyrene diol epoxide-induced DNA damage measured by a host-cell reactivation assay was modulated by two XPD/ERCC2 polymorphisms in lung cancer [18].
  • Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gln allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18-0.89) [4].
  • The second gene is telomeric (in the human) to ERCC2 and contains a motif found in ankyrins, some cell cycle proteins, and transcription factors [19].
 

Anatomical context of ERCC2

 

Associations of ERCC2 with chemical compounds

  • XPD/ERCC2 is a helicase involved in the nucleotide excision repair pathway, which recognizes and repairs many structurally unrelated lesions, such as bulky adducts and thymidine dimers [5].
  • We have evaluated host cell reactivation and cell survival of wild type Chinese hamster ovary cells and of mutants in the NER-genes ERCC1, ERCC2, and ERCC4 after treatment with the methylating compounds dimethylsulfate and methylnitrosourea [25].
  • RESULTS: The rank ordering of sensitivity to both 4HC and PM, based on the combined survival data, was UV41/UV4/UV20 > > UV61/UV24/UV135/EM9 > or = UV5 approximately AA8 [26].
  • Protein expression was also compared with a pre-defined categorisation of the standard agents into six mechanism-of-action (MOA) groups resulting in an inverse association between XPD and alkylating agent sensitivity [27].
  • In 42 healthy Japanese non-smoking men, we investigated the relationship between the MN frequency levels and genetic polymorphisms in three different genes: aldehyde dehydrogenase 2 (ALDH2), X-ray repair cross-complementing group 1 (XRCC1) and excision repair cross-complementing group 2 (ERCC2) [28].
 

Physical interactions of ERCC2

  • Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH [29].
 

Regulatory relationships of ERCC2

  • Furthermore, we show that gammaH2Ax, DSBs, and RAD51 foci are synergistically induced in EM9 cells with camptothecin, suggesting that lack of SSB repair in EM9 causes more collapsed forks and more recombination repair [30].
  • We have investigated both DNA ligase activities and a protein which stimulates DNA ligase activity in mutant EM9 cells, XRCC1-transfectant H9T3-7-1 cells and wild-type AA8 cells [31].
 

Other interactions of ERCC2

 

Analytical, diagnostic and therapeutic context of ERCC2

References

  1. The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. Schaeffer, L., Moncollin, V., Roy, R., Staub, A., Mezzina, M., Sarasin, A., Weeda, G., Hoeijmakers, J.H., Egly, J.M. EMBO J. (1994) [Pubmed]
  2. Chromosome 19q deletions in human gliomas overlap telomeric to D19S219 and may target a 425 kb region centromeric to D19S112. Yong, W.H., Chou, D., Ueki, K., Harsh, G.R., von Deimling, A., Gusella, J.F., Mohrenweiser, H.W., Louis, D.N. J. Neuropathol. Exp. Neurol. (1995) [Pubmed]
  3. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Damaraju, S., Murray, D., Dufour, J., Carandang, D., Myrehaug, S., Fallone, G., Field, C., Greiner, R., Hanson, J., Cass, C.E., Parliament, M. Clin. Cancer Res. (2006) [Pubmed]
  4. Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China. Shen, M., Berndt, S.I., Rothman, N., Demarini, D.M., Mumford, J.L., He, X., Bonner, M.R., Tian, L., Yeager, M., Welch, R., Chanock, S., Zheng, T., Caporaso, N., Lan, Q. Int. J. Cancer (2005) [Pubmed]
  5. XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review. Manuguerra, M., Saletta, F., Karagas, M.R., Berwick, M., Veglia, F., Vineis, P., Matullo, G. Am. J. Epidemiol. (2006) [Pubmed]
  6. A role of the C-terminal part of p44 in the promoter escape activity of transcription factor IIH. Tremeau-Bravard, A., Perez, C., Egly, J.M. J. Biol. Chem. (2001) [Pubmed]
  7. Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B[a]PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers. Pavanello, S., Pulliero, A., Siwinska, E., Mielzynska, D., Clonfero, E. Carcinogenesis (2005) [Pubmed]
  8. Lethality in yeast of trichothiodystrophy (TTD) mutations in the human xeroderma pigmentosum group D gene. Implications for transcriptional defect in TTD. Guzder, S.N., Sung, P., Prakash, S., Prakash, L. J. Biol. Chem. (1995) [Pubmed]
  9. Correlates of delayed referral for the diagnosis of dementia in an outpatient population. Cattel, C., Gambassi, G., Sgadari, A., Zuccalà, G., Carbonin, P., Bernabei, R. J. Gerontol. A Biol. Sci. Med. Sci. (2000) [Pubmed]
  10. Myocardial and peripheral vascular functional adaptation to exercise training. Hannukainen, J.C., Janatuinen, T., Toikka, J.O., Järvisalo, M.J., Heinonen, O.J., Kapanen, J., Någren, K., Nuutila, P., Kujala, U.M., Kaprio, J., Knuuti, J., Kalliokoski, K.K. Scandinavian journal of medicine & science in sports (2007) [Pubmed]
  11. A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Giglia-Mari, G., Coin, F., Ranish, J.A., Hoogstraten, D., Theil, A., Wijgers, N., Jaspers, N.G., Raams, A., Argentini, M., van der Spek, P.J., Botta, E., Stefanini, M., Egly, J.M., Aebersold, R., Hoeijmakers, J.H., Vermeulen, W. Nat. Genet. (2004) [Pubmed]
  12. XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha. Keriel, A., Stary, A., Sarasin, A., Rochette-Egly, C., Egly, J.M. Cell (2002) [Pubmed]
  13. Polymorphisms in nucleotide excision repair genes and risk of multiple primary melanoma: the Genes Environment and Melanoma Study. Millikan, R.C., Hummer, A., Begg, C., Player, J., de Cotret, A.R., Winkel, S., Mohrenweiser, H., Thomas, N., Armstrong, B., Kricker, A., Marrett, L.D., Gruber, S.B., Culver, H.A., Zanetti, R., Gallagher, R.P., Dwyer, T., Rebbeck, T.R., Busam, K., From, L., Mujumdar, U., Berwick, M. Carcinogenesis (2006) [Pubmed]
  14. Regulation of cisplatin resistance and homologous recombinational repair by the TFIIH subunit XPD. Aloyz, R., Xu, Z.Y., Bello, V., Bergeron, J., Han, F.Y., Yan, Y., Malapetsa, A., Alaoui-Jamali, M.A., Duncan, A.M., Panasci, L. Cancer Res. (2002) [Pubmed]
  15. Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations. Banerjee, M., Sarkar, J., Das, J.K., Mukherjee, A., Sarkar, A.K., Mondal, L., Giri, A.K. Carcinogenesis (2007) [Pubmed]
  16. Enhancing alkylating agent resistance through ERCC2 gene transfection in human glioma cell line. Chen, Z., Zhang, J., Mohr, G. Chin. Med. J. (2003) [Pubmed]
  17. A long-range restriction map of the human chromosome 19q13 region: close physical linkage between CKMM and the ERCC1 and ERCC2 genes. Smeets, H., Bachinski, L., Coerwinkel, M., Schepens, J., Hoeijmakers, J., van Duin, M., Grzeschik, K.H., Weber, C.A., de Jong, P., Siciliano, M.J. Am. J. Hum. Genet. (1990) [Pubmed]
  18. Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes. Qiao, Y., Spitz, M.R., Shen, H., Guo, Z., Shete, S., Hedayati, M., Grossman, L., Mohrenweiser, H., Wei, Q. Carcinogenesis (2002) [Pubmed]
  19. Sequence analysis of the ERCC2 gene regions in human, mouse, and hamster reveals three linked genes. Lamerdin, J.E., Stilwagen, S.A., Ramirez, M.H., Stubbs, L., Carrano, A.V. Genomics (1996) [Pubmed]
  20. Expression of excision repair genes in non-malignant bone marrow from cancer patients. Dabholkar, M., Bostick-Bruton, F., Weber, C., Egwuagu, C., Bohr, V.A., Reed, E. Mutat. Res. (1993) [Pubmed]
  21. Associations between XRCC1 and ERCC2 polymorphisms and DNA damage in peripheral blood lymphocyte among coke oven workers. Leng, S., Cheng, J., Pan, Z., Huang, C., Niu, Y., Dai, Y., Li, B., He, F., Zheng, Y. Biomarkers (2004) [Pubmed]
  22. The DNA repair genes XPB and XPD defend cells from retroviral infection. Yoder, K., Sarasin, A., Kraemer, K., McIlhatton, M., Bushman, F., Fishel, R. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  23. Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus x protein in liver cells and transgenic liver tissue. Jaitovich-Groisman, I., Benlimame, N., Slagle, B.L., Perez, M.H., Alpert, L., Song, D.J., Fotouhi-Ardakani, N., Galipeau, J., Alaoui-Jamali, M.A. J. Biol. Chem. (2001) [Pubmed]
  24. 8-Oxoguanine DNA Glycosylase and MutY Homolog Are Involved in the Incision of Arsenite-Induced DNA Adducts. Pu, Y.S., Jan, K.Y., Wang, T.C., Wang, A.S., Gurr, J.R. Toxicol. Sci. (2007) [Pubmed]
  25. Proficient deoxyribonucleic acid repair of methylation damage in hamster ERCC-gene mutants. Nexø, B.A., Dybdahl, M., Damgaard, J., Olsen, L.S., Møller, P., Wassermann, K. Mutat. Res. (1998) [Pubmed]
  26. Nucleotide excision repair genes as determinants of cellular sensitivity to cyclophosphamide analogs. Andersson, B.S., Sadeghi, T., Siciliano, M.J., Legerski, R., Murray, D. Cancer Chemother. Pharmacol. (1996) [Pubmed]
  27. Nucleotide excision repair protein levels vis-à-vis anticancer drug resistance in 60 human tumor cell lines. Chen, Z.P., Malapetsa, A., Monks, A., Myers, T.G., Mohr, G., Sausville, E.A., Scudiero, D.A., Panasci, L.C. Ai Zheng (2002) [Pubmed]
  28. Effects of ALDH2 gene polymorphisms and alcohol-drinking behavior on micronuclei frequency in non-smokers. Ishikawa, H., Yamamoto, H., Tian, Y., Kawano, M., Yamauchi, T., Yokoyama, K. Mutat. Res. (2003) [Pubmed]
  29. Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH. Reardon, J.T., Ge, H., Gibbs, E., Sancar, A., Hurwitz, J., Pan, Z.Q. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  30. Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Saleh-Gohari, N., Bryant, H.E., Schultz, N., Parker, K.M., Cassel, T.N., Helleday, T. Mol. Cell. Biol. (2005) [Pubmed]
  31. Altered DNA ligase III activity in the CHO EM9 mutant. Ljungquist, S., Kenne, K., Olsson, L., Sandström, M. Mutat. Res. (1994) [Pubmed]
  32. The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. Wang, X.W., Vermeulen, W., Coursen, J.D., Gibson, M., Lupold, S.E., Forrester, K., Xu, G., Elmore, L., Yeh, H., Hoeijmakers, J.H., Harris, C.C. Genes Dev. (1996) [Pubmed]
  33. Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. Broberg, K., Björk, J., Paulsson, K., Höglund, M., Albin, M. Carcinogenesis (2005) [Pubmed]
  34. Genotyping of patients with sporadic and radiation-associated meningiomas. Sadetzki, S., Flint-Richter, P., Starinsky, S., Novikov, I., Lerman, Y., Goldman, B., Friedman, E. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  35. Polymorphisms in the two helicases ERCC2/XPD and ERCC3/XPB of the transcription factor IIH complex and risk of lung cancer: a case-control analysis in a Chinese population. Hu, Z., Xu, L., Shao, M., Yuan, J., Wang, Y., Wang, F., Yuan, W., Qian, J., Ma, H., Wang, Y., Liu, H., Chen, W., Yang, L., Jing, G., Huo, X., Chen, F., Jin, L., Wei, Q., Wu, T., Lu, D., Huang, W., Shen, H. Cancer Epidemiol. Biomarkers Prev. (2006) [Pubmed]
  36. Complementation of repair gene mutations on the hemizygous chromosome 9 in CHO: a third repair gene on human chromosome 19. Thompson, L.H., Bachinski, L.L., Stallings, R.L., Dolf, G., Weber, C.A., Westerveld, A., Siciliano, M.J. Genomics (1989) [Pubmed]
 
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