Melanoma is the most devastating form of
skin cancer. The steady increase in the incidence of
melanoma, its resistance to
chemotherapy, together with its high potential to metastasize, have emphasized the importance of its prevention. It is becoming clear that solar ultraviolet radiation is a main culprit in the etiology of
melanoma, the same as in basal and
squamous cell carcinomas. It is commonly accepted that skin pigmentation and
melanin content are principal determinants of the susceptibility to
melanoma and other sun-induced
skin cancers. Although this is generally true, however, prediction of
melanoma risk based solely on pigmentary phenotype is not always precise and fails to identify high-risk individuals with dark skin color. Other important risk factors need to be considered and better defined, particularly DNA repair capacity. Emerging studies have revealed the role of
melanoma susceptibility genes in regulating DNA repair, and indicated that
melanoma patients have a lower DNA repair capacity than the general population. As the response of human melanocytes to ultraviolet radiation is modulated by an array of paracrine factors, we have focused our investigation on the role of
melanocortins and the
melanocortin 1 receptor, as well as
endothelin-1, in this response. We have discovered novel roles for
melanocortins and
endothelin-1 as survival factors that rescue human melanocytes from ultraviolet radiation-induced apoptosis, and importantly enhance repair of
DNA photoproducts and reduce the release of
hydrogen peroxide that can cause oxidative stress. Our findings, together with epidemiological data showing that loss-of-function mutations in the
melanocortin-1 receptor gene increase the risk of
melanoma, substantiate the role of DNA repair in
melanoma genesis, and suggest that responsiveness to
melanocortins and
endothelin-1 is important for
melanoma prevention.