title: Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes.
abstract: Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)-induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR-induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR-induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR-induced DNA damage in melanocytes.
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Hauser
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Kadekaro
authors.forename: Renny J
authors.initials: RJ
authors.lastname: Kavanagh
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
authors.forename: Silva
authors.initials: S
authors.lastname: Terzieva
authors.forename: Sandy
authors.initials: S
authors.lastname: Schwemberger
authors.forename: George
authors.initials: G
authors.lastname: Babcock
authors.forename: M B
authors.initials: MB
authors.lastname: Rao
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.forename: Zalfa A
authors.initials: ZA
authors.lastname: Abdel-Malek
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000528:radiation effects; D001706:Biopsy; D002455:Cell Division / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D008543:Melanins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology* / Q000528:radiation effects*; D008545:Melanoma / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D011740:Pyrimidine Dimers / Q000096:biosynthesis / Q000528:radiation effects; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism / Q000502:physiology*; D012307:Risk Factors; D012867:Skin / Q000166:cytology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D008543:Melanins; D011740:Pyrimidine Dimers; D044102:Receptor, Melanocortin, Type 1; C018362:pheomelanin; C041877:eumelanin; D006861:Hydrogen Peroxide