The melanocortin-1 receptor: A key melanoma risk determinant and a critical regulator of the UV DNA damage repair response

Malignant melanoma of the skin represents one of the most aggressive and deadly malignancies, affecting persons of all ages with increasing frequency. Ultraviolet radiation (UV) is a major etiological risk factor, but despite public educational campaigns aimed at limiting UV exposure, melanoma incidence has been steadily increasing for several decades. The melanocortin-1 receptor (MC1R) has emerged as a major genetic risk factor of melanoma. It encodes a Gs-protein coupled receptor expressed on the surface of the melanocytes that relays survival and differentiation signals to melanocytes through the second messenger cAMP. The MC1R gene is highly polymorphic with variant alleles linked with red hair, fair skin, poor UV tanning, and elevated melanoma risk. MC1R activation after UV exposure results in adaptive melanization (tanning) to provide enhanced protection against cutaneous UV penetration and damage. Defective MC1R signaling results in inadequate melanization of the skin, which allows UV-induced DNA changes to accumulate that can lead to mutations and carcinogenesis. However, MC1R signaling also protects against UV-mediated carcinogenesis independent of pigmentation, suggesting other roles for MC1R in the UV DNA damage response. This review assesses the consequences of MC1R allelic variants in light of the newly identified crosstalk between MC1R signaling and melanocytic DNA repair.