Additional Supporting Information may be found in the online version of this article.
Novel XPG (ERCC5) Mutations Affect DNA Repair and Cell Survival after Ultraviolet but not Oxidative Stress
Article first published online: 17 JAN 2013
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 3, pages 481–489, March 2013
How to Cite
Soltys, D. T., Rocha, C. R. R., Lerner, L. K., de Souza, T. A., Munford, V., Cabral, F., Nardo, T., Stefanini, M., Sarasin, A., Cabral-Neto, J. B. and Menck, C. F. M. (2013), Novel XPG (ERCC5) Mutations Affect DNA Repair and Cell Survival after Ultraviolet but not Oxidative Stress. Hum. Mutat., 34: 481–489. doi: 10.1002/humu.22259
Communicated by Riccardo Fodde
- Issue published online: 18 FEB 2013
- Article first published online: 17 JAN 2013
- Accepted manuscript online: 15 DEC 2012 10:10PM EST
- Manuscript Accepted: 30 NOV 2012
- Manuscript Received: 29 JUL 2012
- Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo, Brazil)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brasília, DF, Brazil)
- Associazione Italiana per la Ricerca sul Cancro (Milan, Italy)
- DNA repair;
- XPG endonuclease;
- UV light;
- oxidative stress;
- xeroderma pigmentosum
Nucleotide excision repair (NER) is the most flexible of all known DNA-repair mechanisms, and XPG is a 3′-endonuclease that participates in NER. Mutations in this gene (ERCC5) may result in the human syndrome xeroderma pigmentosum (XP) and, in some cases, in the complex phenotype of Cockayne syndrome (CS). Two Brazilian XP siblings, who were mildly affected, were investigated and classified into the XP-G group. The cells from these patients were highly ultraviolet (UV) sensitive but not sensitive to photosensitized methylene blue, an agent that causes oxidative stress. This phenotype is in contrast to XP-G/CS cells, which are highly sensitive to this oxidative agent. Sequencing revealed a compound heterozygous genotype with two novel missense mutations: c.83C>A (p.Ala28Asp) and c.2904G>C (p.Trp968Cys). The first mutation maps to the catalytic site of the XPG protein, whereas the second may compromise binding to DNA. Functional assays indicated that the mutated alleles were unable to perform the complete repair of UV-irradiated plasmids; however, full correction was observed for oxidatively damaged plasmids. Therefore, the XP phenotype of these patients is caused by novel missense mutations that specifically affect DNA repair for UV- but not oxidative-stress-induced DNA damage, and implications for XP versus XP/CS phenotype are discussed.