Significance of the melanocortin 1 receptor in the DNA damage response of human melanocytes to ultraviolet radiation.

Activation of the melanocortin 1 receptor (MC1R) by -melanocortin (-MSH) stimulates eumelanin synthesis and enhances repair of ultraviolet radiation (UV)-induced DNA damage. We report on the DNA damage response (DDR) of human melanocytes to UV and its enhancement by -MSH. -MSH up-regulated the levels of XPC, the enzyme that recognizes DNA damage sites, enhanced the UV-induced phosphorylation of the DNA damage sensors ataxia telangiectasia and Rad3-related (ATR) and ataxia telangiectasia mutated (ATM) and their respect-ive substrates checkpoint kinases 1 and 2, and increased phosphorylated H2AX (H2AX) formation. These effects required functional MC1R and were absent in melanocytes expressing loss of function (LOF) MC1R. The levels of wild-type p53-induced phosphatase 1 (Wip1), which dephosphorylates H2AX, correlated inversely with H2AX. We propose that -MSH increases UV-induced H2AX to facilitate formation of DNA repair complexes and repair of DNA photoproducts, and LOF of MC1R compromises the DDR and genomic stability of melanocytes.