The MC1R gene is highly polymorphic in European populations, with three common alleles highly penetrant for red hair, fair skin, inability to tan, and increased risk of developing skin cancers (RHC alleles). Carriers of low penetrant alleles (r) show intermediate responses to UV compared to MC1R-WT and RHC variants. Notably the induction of Dopachrome tautomerase (DCT) is compromised in RHC variant human melanocyte strains grown in culture. MC1R-WT melanoblast (MB) cells treated with DCT-siRNA and UVR exposure showed reduced cell survival. Expression of p53/pp53 increased after DCT siRNA treatment, UVR irradiation, or both. Knockdown of DCT appeared to negatively affect DNA damage responses via p53 in melanoma cell lines and MC1R-WT MB cell strains in monoculture. MC1R-RHC variant MB strains showed negligible responses including reduction in DCT, with subsequent increases in p53/pp53. The effect of knockdown of DCT expression using lentivirus particles containing hairpin shRNA against human DCT in co-cultures of MC1R-WT MB cells and keratinocytes showed the reduction in DCT protein levels, changes in cell survival, and levels of p53, p38 and other proteins were not as great as that seen in the monoculture experiments. It is possible that keratinocytes conferred a protective function to the MB in co-culture, allowing increased survival post-UVR, and reduced DNA damage, thus requiring less increase in expression of proteins such as p53 and p38. Assay of H2O2 found that this increased in MC1R-WT MB cells after DCT-siRNA and UVR treatment in monoculture. Without functional DCT protein, the cells were more sensitive to oxidative as well as DNA damage. One of the mechanisms whereby MC1R variants result in increased sun sensitivity of the skin is that the loss of DCT results in reduced increases in DNA damage response proteins, indirectly contributing to the accumulation of mutations that may eventually lead to melanoma.