The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial 
role in human and mouse pigmentation. Activation of MC1R in melanocytes by 
α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signalling and melanin 
production and enhances DNA repair after ultraviolet irradiation. Individuals 
carrying MC1R variants, especially those associated with red hair colour, fair 
skin and poor tanning ability (denoted as RHC variants), are associated with 
higher risk of melanoma. However, how MC1R activity is modulated by ultraviolet 
irradiation, why individuals with red hair are more prone to developing 
melanoma, and whether the activity of RHC variants might be restored for 
therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted 
intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC 
variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R 
palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is 
essential for activating MC1R signalling, which triggers increased pigmentation, 
ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and 
melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which 
endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show 
that pharmacological activation of palmitoylation rescues the defects of Mc1r 
RHC variants and prevents melanomagenesis. The results highlight a central role 
for MC1R palmitoylation in pigmentation and protection against melanoma.