title: 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.
authors.affiliation: Melanogenix Group, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Shu Shyan
authors.initials: SS
authors.lastname: Wong
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ainger
authors.forename: J Helen
authors.initials: JH
authors.lastname: Leonard
authors.forename: Richard A
authors.initials: RA
authors.lastname: Sturm
mesh_terms: D000483:Alleles; D002478:Cells, Cultured; D018920:Coculture Techniques; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes; D008544:Melanocytes / Q000187:drug effects / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects
chemical_list: C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D044102:Receptor, Melanocortin, Type 1; D016159:Tumor Suppressor Protein p53; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D048051:p38 Mitogen-Activated Protein Kinases