Melanin content and MC1R function independently affect UVR‐induced DNA damage in cultured human melanocytes

Summary Malignant transformation of melanocytes leads tomelanoma, the most fatal form of skin cancer. Ultra-violet radiation (UVR)-induced DNA photoproductsplay an important role in melanomagenesis. Cutane-ous melanin content represents a major photopro-tective mechanism against UVR-induced DNAdamage, and generally correlates inversely with therisk of skin cancer, including melanoma. Melanomarisk is also determined by susceptibility genes, oneof which is the melanocortin 1 receptor (MC1R)gene. Certain MC1R alleles are strongly associatedwith melanoma. We hereby present experimentalevidence for the role of two melanoma risk factors,constitutive pigmentation, as assessed by total mel-anin, eumelanin and pheomelanin contents, andMC1R genotype and function, in determining theinduction and repair of DNA photoproducts in cul-tured human melanocytes after irradiation withincreasing doses of UVR. We found that total mel-anin and eumelanin contents (MC and EC) correla-ted inversely with the extent of UVR-inducedgrowth arrest, apoptosis and induction of cyclobu-tane pyrimidine dimers (CPD), but not with hydro-gen peroxide release in melanocytes expressingfunctional MC1R. In comparison, melanocytes withloss-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 independentdeterminants of UVR-induced DNA damage in mel-anocytes.Key words: human melanocytes/melanoma/ultravioletradiation/cyclobutane pyrimidine/dimers/melanin/eumela-nin/melanocortin 1 receptorReceived 16 December 2005; revised and accepted forpublication 21 January 2006