New functions of XPC in the protection of human skin cells from oxidative damage.
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.
D'Errico
Mariarosaria
M
Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
Parlanti
Eleonora
E
Teson
Massimo
M
de Jesus
Bruno M Bernardes
BM
Degan
Paolo
P
Calcagnile
Angelo
A
Jaruga
Pawel
P
Bjørås
Magnar
M
Crescenzi
Marco
M
Pedrini
Antonia M
AM
Egly
Jean-Marc
JM
Zambruno
Giovanna
G
Stefanini
Miria
M
Dizdaroglu
Miral
M
Dogliotti
Eugenia
E
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
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