Defining the role of MC1R in UV-induced oxidative damage and DNA repair

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DESCRIPTION (provided by applicant): We are interested in deciphering the molecular basis of UV injury and carcinogenesis in the skin, with the long- term research objective of designing chemoprotective strategies against skin cancer. Fair skin correlates with enhanced expression of pheomelanin, a pigment with poor UV-blocking abilities, and reduced expression of eumelanin, a pigment with excellent UV-blocking properties. Logically, pheomelanotic individuals endure the highest incidence of UV-mediated damage, including skin cancer. Pigmentation is regulated by the binding of melanocortin stimulating hormone (MSH) to its cognate receptor, the melanocortin-1 receptor (MC1R), which in turn mediates adenylyl cyclase activation and subsequent production of cyclic AMP (cAMP). High functioning MC1R variants result in high levels of cAMP and eumelaninization, whereas low functioning MC1R variants lead to low levels of cAMP and pheomelanization. We have developed a novel mouse model that mimics human skin of different pigmentation (eumelanotic, pheomelanotic, and albino). We found that by topically applying a small molecule (forskolin) to the fair-skinned animals, eumelanin production was induced and the animals were UV-protected. Such forskolin-mediated eumelanin production likely occurs by directly activating adenylyl cyclase in melanocytes, thereby "by-passing" the defective MC1R signaling that causes fair skin in our model. We hypothesize that MC1R dysfunction leads to UV-dependent oxidative damage in the skin and defective repair of UV-mediated DNA damage. Further, we propose that topical forskolin protects against UV injury through eumelanin induction and rescue of DNA repair. Taking advantage of our unique murine model, we will determine the effect of pheomelanin on UV damage in the skin (Specific Aim aim 1), and define the contribution of MC1R function in the repair of UV-mediated damage (Specific Aim aim 2). In our studies, we will measure different types of UV-induced oxidative damage, analyze repair of this damage, and determine whether topical forskolin can modify these damage and repair profiles. Our findings will have significant health relatedness, as they will clarify longstanding questions regarding pheomelanin in oxidative damage and MC1R function in the repair of UV-induced damage. Most importantly, we anticipate that our resulting data will provide clear insight into effective, topical approaches to repairing UV-mediated skin damage and preventing skin cancer.