title: Significance of the melanocortin 1 receptor in the DNA damage response of human melanocytes to ultraviolet radiation.
abstract: Activation of the melanocortin 1 receptor (MC1R) by α-melanocortin (α-MSH) stimulates eumelanin synthesis and enhances repair of ultraviolet radiation (UV)-induced DNA damage. We report on the DNA damage response (DDR) of human melanocytes to UV and its enhancement by α-MSH. α-MSH up-regulated the levels of XPC, the enzyme that recognizes DNA damage sites, enhanced the UV-induced phosphorylation of the DNA damage sensors ataxia telangiectasia and Rad3-related (ATR) and ataxia telangiectasia mutated (ATM) and their respect-ive substrates checkpoint kinases 1 and 2, and increased phosphorylated H2AX (γH2AX) formation. These effects required functional MC1R and were absent in melanocytes expressing loss of function (LOF) MC1R. The levels of wild-type p53-induced phosphatase 1 (Wip1), which dephosphorylates γH2AX, correlated inversely with γH2AX. We propose that α-MSH increases UV-induced γH2AX to facilitate formation of DNA repair complexes and repair of DNA photoproducts, and LOF of MC1R compromises the DDR and genomic stability of melanocytes.
authors.affiliation: Department of Dermatology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Viki
authors.initials: V
authors.lastname: Swope
authors.forename: Christina
authors.initials: C
authors.lastname: Alexander
authors.forename: Renny
authors.initials: R
authors.lastname: Starner
authors.forename: Sandy
authors.initials: S
authors.lastname: Schwemberger
authors.forename: George
authors.initials: G
authors.lastname: Babcock
authors.forename: Zalfa A
authors.initials: ZA
authors.lastname: Abdel-Malek
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D042822:Genomic Instability / Q000528:radiation effects*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008544:Melanocytes / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation / Q000528:radiation effects; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D044102:Receptor, Melanocortin, Type 1; C086984:XPC protein, human; D000521:alpha-MSH; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: DNA damage response; DNA photoproducts; melanocytes, melanocortin 1 receptor; ultraviolet radiation; α-melanocortin