Title: Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts.
Authors: Wang, Hsiang-Tsui; Choi, Bongkun; Tang, Moon-shong
Published In Proc Natl Acad Sci U S A, (2010 Jul 6)
Abstract: Melanomas occur mainly in sunlight-exposed skin. Xeroderma pigmentosum (XP) patients have 1,000-fold higher incidence of melanoma, suggesting that sunlight-induced "bulky" photoproducts are responsible for melanomagenesis. Sunlight induces a high level of reactive oxygen species in melanocytes (MCs); oxidative DNA damage (ODD) may thus also contribute to melanomagenesis, and XP gene products may participate in the repair of ODD. We examined the effects of melanin on UVA (320-400 nm) irradiation-induced ODD and UV photoproducts and the repair capacity in MC and XP cells for ODD and UV-induced photoproducts. Our findings indicate that UVA irradiation induces a significantly higher amount of formamidopyrimidine glycosylase-sensitive ODD in MCs than in normal human skin fibroblasts (NHSFs). In contrast, UVA irradiation induces an insignificant amount of UvrABC-sensitive sites in either of these two types of cells. We also found that, compared to NHSFs, MCs have a reduced repair capacity for ODD and photoproducts; H(2)O(2) modified- and UVC-irradiated DNAs induce a higher mutation frequency in MCs than in NHSFs; and, XP complementation group A (XPA), XP complementation group C, and XP complementation group G cells are deficient in ODD repair and ODD induces a higher mutation frequency in XPA cells than in NHSFs. These results suggest that: (i) melanin sensitizes UVA in the induction of ODD but not bulky UV photoproducts; (ii) the high susceptibility to UVA-induced ODD and the reduced DNA repair capacity in MCs contribute to carcinogenesis; and (iii) the reduced repair capacity for ODD contributes to the high melanoma incidence in XP patients.
PubMed ID: 20566850
MeSH Terms: Cells, Cultured; DNA Damage*; DNA Repair*; DNA-Formamidopyrimidine Glycosylase/metabolism; Deoxyguanosine/analogs & derivatives; Deoxyguanosine/metabolism; Dose-Response Relationship, Drug; Fibroblasts/cytology; Fibroblasts/metabolism; Humans; Hydrogen Peroxide/pharmacology; Melanins/pharmacology; Melanocytes/cytology; Melanocytes/metabolism*; Oxidants/pharmacology; Oxidative Stress/drug effects; Oxidative Stress/physiology*; Oxidative Stress/radiation effects; Skin/cytology; Ultraviolet Rays