MC1R Variant Allele Effects on UVR-Induced Phosphorylation of p38, p53, and DDB2 Repair Protein Responses in Melanocytic Cells in Culture

Abstract

Variant alleles of the human melanocortin 1 receptor (MC1R) reduce the ability of melanocytes to produce the dark pigment eumelanin, with R alleles being most deficient. Cultured melanocytes of MC1R R/R variant genotype give reduced responses to [Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-MSH) ligand stimulation and lower levels of DNA repair than MC1R wild-type strains. p38 controls xeroderma pigmentosum (XP)-C recruitment to DNA damage sites through regulating ubiquitylation of the DNA damage-binding protein 2 (DDB2) protein, and p53 is implicated in the nuclear excision repair process through its regulation of XP-C and DDB2 protein expression. We report the effects of MC1R ligand treatment and UVR exposure on phosphorylation of p38 and p53, and DDB2 protein expression in MC1R variant strains. Wild-type MC1R melanocyte strains grown together with keratinocytes in coculture, when treated with NDP-MSH and exposed to UVR, gave synergistic activation of p38 and p53 phosphorylation, and were not replicated by R/R variant melanocytes, which have lower basal levels of phosphorylated forms of p38. Minor increases in p38 phosphorylation status in R/R variant melanocyte cocultures could be attributed to the keratinocytes alone. We also found that MC1R wild-type strains regulate DDB2 protein levels through p38, but MC1R R/R variant melanocytes do not. This work confirms the important functional role that the MC1R receptor plays in UVR stress-induced DNA repair.

A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots

“…Therefore, it could be hypothesized that a less effective repair of UV induced DNA damage explains the skin color independent effects of skin color genes in pigmented spots and skin cancer. In support of this, MC1R loss of function alleles have been associated with a higher level of UV induced DNA damage in melanocytes (April and Barsh, 2007;Wong et al, 2012), which is independent of total melanin content (Hauser et al, 2006). Possibly, the melanocytes react to DNA damage by locally boosting melanin production, to provide a subsequent UV protection.…”

UV Radiation and the Skin

“…The most prevalent MC1R mutations (D84E, R151C, R160W and D294H) are commonly referred to as “RHC” (red hair color) alleles because of their association with red hair color, freckling and tendency to burn after UV exposure [199,200]. Loss of signaling MC1R alleles such as the RHC variants are associated with up to a four-fold increased lifetime risk of melanoma and other skin cancers [201–203]. Overall, there is much evidence placing MC1R as a critical determinant of skin cancer risk, and regulation of eumelanin by POMC derived peptides depends on genetic context [204].…”

Melanocortins and the melanocortin 1 receptor, moving translationally towards melanoma prevention

“…Conversely, Nutlin-3, the inhibitor of MDM2, the ubiquitin ligase that degrads p53, reduced oxidative damage. Treatment of human melanocytes expressing functional MC1R enhanced the UV-induced activation of the stress-activated MAP kinases p38 [55,128], which in turn activates transcription factors that are involved in the DNA damage response (DDR), such as p53 and ATF-2.…”