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Gene Review

ERCC6  -  excision repair cross-complementation group 6

Homo sapiens

Synonyms: ARMD5, ATP-dependent helicase ERCC6, CKN2, COFS, COFS1, ...
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Disease relevance of ERCC6

  • Allelic loss of 10q is a common genetic event in malignant gliomas, with three 10q tumor suppressor genes, ERCC6, PTEN, and DMBT1, putatively implicated in the most common type of malignant glioma, glioblastoma [1].
  • Proteins encoded by the mfd gene in E. coli and by the ERCC6/CSB gene in humans, both of which possess the so-called helicase motifs, are required for the coupling reaction [2].
  • In this study we overproduced the human CSB protein using the baculovirus vector and purified and characterized the recombinant protein [2].
  • Additionally we have examined interactions between TFIIH components, the human NER protein XPG, and the CSB protein which is implicated in Cockayne syndrome (CS) [3].
  • Higher mRNA levels of Xeroderma pigmentosum group B (XPB), which links DNA repair with DNA transcription, and of Cockayne's syndrome group B (CSB), which is essential for gene-specific repair, were observed in tumor tissues that were clinically resistant to platinum-based chemotherapy, as compared with tissues from patients responding to therapy [4].

High impact information on ERCC6

  • Finally, there are indications that the genes CSA and CSB, which are implicated in the human hereditary disease Cockayne syndrome, may have a role in transcription [5].
  • CSB-deficient mice exhibit all of the CS repair characteristics: ultraviolet (UV) sensitivity, inactivation of transcription-coupled repair, unaffected global genome repair, and inability to resume RNA synthesis after UV exposure [6].
  • In contrast to the human syndrome, CSB-deficient mice show increased susceptibility to skin cancer [6].
  • These observations suggest that the products of the CSA and CSB genes are involved in transcription [7].
  • Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSB) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER [8].

Chemical compound and disease context of ERCC6


Biological context of ERCC6


Anatomical context of ERCC6


Associations of ERCC6 with chemical compounds

  • When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively) [19].
  • Melatonin further and statistical significantly up-regulated ERCC6 mRNA expression in the peri-ischemic region of rat brains [20].
  • We previously reported that the CSB protein is involved in cellular repair of 8-hydroxyguanine, an abundant lesion in oxidatively damaged DNA and that the putative helicase motif V/VI of the CSB may play a role in this process [21].
  • The present study investigated the role of the CSB protein in cellular repair of 8-hydroxyadenine (8-OH-Ade), another abundant lesion in oxidatively damaged DNA [21].
  • By site-directed mutagenesis the invariant lysine residue in the NTP-binding motif of CSB was substituted with a physicochemically related arginine [22].

Physical interactions of ERCC6

  • XPG binds transcription-sized DNA bubbles through two domains not required for incision and functionally interacts with CSB on these bubbles to stimulate its ATPase activity [23].

Regulatory relationships of ERCC6

  • Activation of p53 would inhibit CSB, stalling transcription complexes and locally blocking chromatin condensation [24].

Other interactions of ERCC6

  • Together, these results implicate coordinated recognition of stalled transcription by XPG and CSB in TCR initiation and suggest that TFIIH-dependent remodeling of stalled RNAPII without release may be sufficient to allow repair [23].
  • Deletion mapping demonstrated 10q loss in 14 of 67 informative cases, with the PTEN and DMBT1 regions involved in all deletions but with the ERCC6 locus spared in two cases [1].
  • Here we have extended these studies to compare low-grade tumors to high-grade tumors and to include ERCC3 (which links DNA repair with DNA transcription) and ERCC6 (which is essential for gene-specific repair) [25].
  • CSB cells exhibited rapid repair near the transcription initiation site but were deficient in repair of sequences encountered by RNA polymerase during elongation (beginning at position +20) [16].
  • Bioinformatics indicated a putative binding-element alteration on the sequence containing C-6530>G SNP in the 5' flanking region of ERCC6 from Sp1 on the C allele to SP1, GATA-1, and OCT-1 on the G allele [18].

Analytical, diagnostic and therapeutic context of ERCC6


  1. PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Sasaki, H., Zlatescu, M.C., Betensky, R.A., Ino, Y., Cairncross, J.G., Louis, D.N. Am. J. Pathol. (2001) [Pubmed]
  2. Human transcription-repair coupling factor CSB/ERCC6 is a DNA-stimulated ATPase but is not a helicase and does not disrupt the ternary transcription complex of stalled RNA polymerase II. Selby, C.P., Sancar, A. J. Biol. Chem. (1997) [Pubmed]
  3. Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein. Iyer, N., Reagan, M.S., Wu, K.J., Canagarajah, B., Friedberg, E.C. Biochemistry (1996) [Pubmed]
  4. Increased mRNA levels of xeroderma pigmentosum complementation group B (XPB) and Cockayne's syndrome complementation group B (CSB) without increased mRNA levels of multidrug-resistance gene (MDR1) or metallothionein-II (MT-II) in platinum-resistant human ovarian cancer tissues. Dabholkar, M., Thornton, K., Vionnet, J., Bostick-Bruton, F., Yu, J.J., Reed, E. Biochem. Pharmacol. (2000) [Pubmed]
  5. Relationships between DNA repair and transcription. Friedberg, E.C. Annu. Rev. Biochem. (1996) [Pubmed]
  6. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. van der Horst, G.T., van Steeg, H., Berg, R.J., van Gool, A.J., de Wit, J., Weeda, G., Morreau, H., Beems, R.B., van Kreijl, C.F., de Gruijl, F.R., Bootsma, D., Hoeijmakers, J.H. Cell (1997) [Pubmed]
  7. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Henning, K.A., Li, L., Iyer, N., McDaniel, L.D., Reagan, M.S., Legerski, R., Schultz, R.A., Stefanini, M., Lehmann, A.R., Mayne, L.V., Friedberg, E.C. Cell (1995) [Pubmed]
  8. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Takebayashi, Y., Pourquier, P., Zimonjic, D.B., Nakayama, K., Emmert, S., Ueda, T., Urasaki, Y., Kanzaki, A., Akiyama, S.I., Popescu, N., Kraemer, K.H., Pommier, Y. Nat. Med. (2001) [Pubmed]
  9. The Cockayne syndrome group B DNA repair protein as an anti-cancer target. Lu, Y., Mani, S., Kandimalla, E.R., Yu, D., Agrawal, S., States, J.C., Bregman, D.B. Int. J. Oncol. (2001) [Pubmed]
  10. Different effects of CSA and CSB deficiency on sensitivity to oxidative DNA damage. de Waard, H., de Wit, J., Andressoo, J.O., van Oostrom, C.T., Riis, B., Weimann, A., Poulsen, H.E., van Steeg, H., Hoeijmakers, J.H., van der Horst, G.T. Mol. Cell. Biol. (2004) [Pubmed]
  11. Functional crosstalk between hOgg1 and the helicase domain of Cockayne syndrome group B protein. Tuo, J., Chen, C., Zeng, X., Christiansen, M., Bohr, V.A. DNA Repair (Amst.) (2002) [Pubmed]
  12. Structure and expression of the excision repair gene ERCC6, involved in the human disorder Cockayne's syndrome group B. Troelstra, C., Hesen, W., Bootsma, D., Hoeijmakers, J.H. Nucleic Acids Res. (1993) [Pubmed]
  13. Localization of the nucleotide excision repair gene ERCC6 to human chromosome 10q11-q21. Troelstra, C., Landsvater, R.M., Wiegant, J., van der Ploeg, M., Viel, G., Buys, C.H., Hoeijmakers, J.H. Genomics (1992) [Pubmed]
  14. 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]
  15. The human CSB (ERCC6) gene corrects the transcription-coupled repair defect in the CHO cell mutant UV61. Orren, D.K., Dianov, G.L., Bohr, V.A. Nucleic Acids Res. (1996) [Pubmed]
  16. Sequence-specific and domain-specific DNA repair in xeroderma pigmentosum and Cockayne syndrome cells. Tu, Y., Bates, S., Pfeifer, G.P. J. Biol. Chem. (1997) [Pubmed]
  17. Cooperation of the Cockayne syndrome group B protein and poly(ADP-ribose) polymerase 1 in the response to oxidative stress. Thorslund, T., von Kobbe, C., Harrigan, J.A., Indig, F.E., Christiansen, M., Stevnsner, T., Bohr, V.A. Mol. Cell. Biol. (2005) [Pubmed]
  18. Synergic effect of polymorphisms in ERCC6 5' flanking region and complement factor H on age-related macular degeneration predisposition. Tuo, J., Ning, B., Bojanowski, C.M., Lin, Z.N., Ross, R.J., Reed, G.F., Shen, D., Jiao, X., Zhou, M., Chew, E.Y., Kadlubar, F.F., Chan, C.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer. Gu, J., Zhao, H., Dinney, C.P., Zhu, Y., Leibovici, D., Bermejo, C.E., Grossman, H.B., Wu, X. Clin. Cancer Res. (2005) [Pubmed]
  20. Neuroprotection by melatonin against ischemic neuronal injury associated with modulation of DNA damage and repair in the rat following a transient cerebral ischemia. Sun, F.Y., Lin, X., Mao, L.Z., Ge, W.H., Zhang, L.M., Huang, Y.L., Gu, J. J. Pineal Res. (2002) [Pubmed]
  21. The cockayne syndrome group B gene product is involved in cellular repair of 8-hydroxyadenine in DNA. Tuo, J., Jaruga, P., Rodriguez, H., Dizdaroglu, M., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  22. Biochemical and biological characterization of wild-type and ATPase-deficient Cockayne syndrome B repair protein. Citterio, E., Rademakers, S., van der Horst, G.T., van Gool, A.J., Hoeijmakers, J.H., Vermeulen, W. J. Biol. Chem. (1998) [Pubmed]
  23. Recognition of RNA polymerase II and transcription bubbles by XPG, CSB, and TFIIH: insights for transcription-coupled repair and Cockayne Syndrome. Sarker, A.H., Tsutakawa, S.E., Kostek, S., Ng, C., Shin, D.S., Peris, M., Campeau, E., Tainer, J.A., Nogales, E., Cooper, P.K. Mol. Cell (2005) [Pubmed]
  24. Activation of p53 or loss of the Cockayne syndrome group B repair protein causes metaphase fragility of human U1, U2, and 5S genes. Yu, A., Fan, H.Y., Liao, D., Bailey, A.D., Weiner, A.M. Mol. Cell (2000) [Pubmed]
  25. Comparative analyses of relative ERCC3 and ERCC6 mRNA levels in gliomas and adjacent non-neoplastic brain. Dabholkar, M.D., Berger, M.S., Vionnet, J.A., Overton, L., Thompson, C., Bostick-Bruton, F., Yu, J.J., Silber, J.R., Reed, E. Mol. Carcinog. (1996) [Pubmed]
  26. Molecular cloning of the human DNA excision repair gene ERCC-6. Troelstra, C., Odijk, H., de Wit, J., Westerveld, A., Thompson, L.H., Bootsma, D., Hoeijmakers, J.H. Mol. Cell. Biol. (1990) [Pubmed]
  27. Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum. Colella, S., Nardo, T., Botta, E., Lehmann, A.R., Stefanini, M. Hum. Mol. Genet. (2000) [Pubmed]
  28. The CSB protein actively wraps DNA. Beerens, N., Hoeijmakers, J.H., Kanaar, R., Vermeulen, W., Wyman, C. J. Biol. Chem. (2005) [Pubmed]
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