Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-07, Vol.107 (27), p.12180-12185
• Main Authors: Wang, Hsiang-Tsui, Choi, Bongkun, Tang, Moon-shong, Setlow, Richard B.
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cells; Cells, Cultured; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; DNA; DNA Damage; DNA Repair; DNA-Formamidopyrimidine Glycosylase - metabolism; Dose-Response Relationship, Drug; Fibroblasts - cytology; Fibroblasts - metabolism; Gene expression; Genetic mutation; Genetics; Genomics; Humans; Hydrogen Peroxide - pharmacology; Irradiation; Melanin; Melanins - pharmacology; Melanocytes; Melanocytes - cytology; Melanocytes - metabolism; Melanoma; Oxidants - pharmacology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Oxidative Stress - radiation effects; Skin - cytology; Skin cancer; Sunlight; Tumors; Ultraviolet radiation; Ultraviolet Rays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1005244107

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; H₂O₂ 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.