Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin 
synthesized by epidermal melanocytes and is known to protect against sun-induced 
DNA damage. The synthesis of eumelanin is stimulated by the binding of 
alpha-melanotropin (alpha-melanocyte-stimulating hormone) to the functional 
melanocortin 1 receptor (MC1R) expressed on melanocytes. The human MC1R gene is 
highly polymorphic and certain allelic variants of the gene are associated with 
red hair phenotype, melanoma and non-melanoma skin cancer. The importance of the 
MC1R gene in determining skin cancer risk led us to examine the impact of 
specific polymorphisms in this gene on the responses of human melanocytes to 
alpha-melanotropin and UV radiation. We compared the ability of human melanocyte 
cultures, each derived from a single donor, to respond to alpha-melanotropin 
with dose-dependent stimulation of cAMP formation, tyrosinase activity and 
proliferation. In each of those cultures the MC1R gene was sequenced, and the 
eumelanin and pheomelanin contents were determined. Human melanocytes homozygous 
for Arg160Trp, heterozygous for Arg160Trp and Asp294His, or for Arg151Cys and 
Asp294His substitutions, but not melanocytes homozygous for Val92Met 
substitution, in the MC1R demonstrated a significantly reduced response to 
alpha-melanotropin. Additionally, melanocytes with a non-functional MC1R 
demonstrated a pronounced increase in their sensitivity to the cytotoxic effect 
of UV radiation compared with melanocytes expressing functional MC1R. We 
conclude that loss-of-function mutations in the MC1R gene sensitize human 
melanocytes to the DNA damaging effects of UV radiation, which may increase skin 
cancer risk.