title: New functions of XPC in the protection of human skin cells from oxidative damage.
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.
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: D'Errico
authors.forename: Eleonora
authors.initials: E
authors.lastname: Parlanti
authors.forename: Massimo
authors.initials: M
authors.lastname: Teson
authors.forename: Bruno M Bernardes
authors.initials: BM
authors.lastname: de Jesus
authors.forename: Paolo
authors.initials: P
authors.lastname: Degan
authors.forename: Angelo
authors.initials: A
authors.lastname: Calcagnile
authors.forename: Pawel
authors.initials: P
authors.lastname: Jaruga
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Pedrini
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
authors.forename: Miral
authors.initials: M
authors.lastname: Dizdaroglu
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dogliotti
mesh_terms: D001959:Bromates / Q000633:toxicity; D002478:Cells, Cultured; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D016877:Oxidants / Q000633:toxicity; D012878:Skin Neoplasms / Q000209:etiology; D014965:X-Rays; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics / Q000378:metabolism
chemical_list: D001959:Bromates; D004268:DNA-Binding Proteins; D016877:Oxidants; C019536:potassium bromate; C086985:RAD23A protein, human; C086984:XPC protein, human; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D045643:DNA Repair Enzymes