New functions of XPC in the protection of human skin cells from oxidative damage

Mariarosaria D'Errico, Eleonora Parlanti, Massimo Teson, Bruno M Bernardes De Jesus, Paolo Degan, Angelo Calcagnile, Pawel Jaruga, Magnar Bjørås, Marco Crescenzi, Antonia M. Pedrini, Jean Marc Egly, Giovanna Zambruno, Miria Stefanini, Miral Dizdaroglu, Eugenia Dogliotti

Research output: Contribution to journalArticlepeer-review

Abstract

Xeroderma pigmentosum (XP) C is involved in the recognition of a variety of bulky DNA-distorting lesions in nucleotide excision repair. Here, we show that XPC plays an unexpected and multifaceted role in cell protection from oxidative DNA damage. XP-C primary keratinocytes and fibroblasts are hypersensitive to the killing effects of DNA-oxidizing agents and this effect is reverted by expression of wild-type XPC. Upon oxidant exposure, XP-C primary keratinocytes and fibroblasts accumulate 8,5′-cyclopurine 2′-deoxynucleosides in their DNA, indicating that XPC is involved in their removal. In the absence of XPC, a decrease in the repair rate of 8-hydroxyguanine (8-OH-Gua) is also observed. We demonstrate that XPC-HR23B complex acts as cofactor in base excision repair of 8-OH-Gua, by stimulating the activity of its specific DNA glycosylase OGG1. In vitro experiments suggest that the mechanism involved is a combination of increased loading and turnover of OGG1 by XPC-HR23B complex. The accumulation of endogenous oxidative DNA damage might contribute to increased skin cancer risk and account for internal cancers reported for XP-C patients.

Original languageEnglish
Pages (from-to)4305-4315
Number of pages11
JournalEMBO Journal
Volume25
Issue number18
DOIs
Publication statusPublished - Sep 20 2006

Keywords

  • Cancer
  • DNA repair
  • Keratinocytes
  • Oxidative DNA damage
  • Xeroderma pigmentosum

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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