title: Divergence of cAMP signalling pathways mediating augmented nucleotide excision repair and pigment induction in melanocytes.
abstract: Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are common in UV-sensitive fair-skinned individuals and are associated with blunted cAMP second messenger signalling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signalling positions melanocytes to resist UV injury by upregulating synthesis of UV-blocking eumelanin pigment and by enhancing the repair of UV-induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP-activated protein kinase (protein kinase A)-mediated phosphorylation of the ataxia telangiectasia-mutated and Rad3-related (ATR) protein on the S435 residue. We investigated the interdependence of cAMP-mediated melanin upregulation and cAMP-enhanced DNA repair in primary human melanocytes and a melanoma cell line. We observed that the ATR-dependent molecular pathway linking cAMP signalling to the NER pathway is independent of MITF activation. Similarly, cAMP-mediated upregulation of pigment synthesis is independent of ATR, suggesting that the key molecular events driving MC1R-mediated enhancement of genome maintenance (eg PKA-mediated phosphorylation of ATR) and MC1R-induced pigment induction (eg MITF activation) are distinct.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Wolf Horrell
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Jarrett
authors.affiliation: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Carter
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.|Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.|Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.|Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: D'Orazio
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007980:Levodopa / Q000737:chemistry; D008543:Melanins / Q000737:chemistry; D008544:Melanocytes / Q000166:cytology*; D016296:Mutagenesis; D009711:Nucleotides / Q000737:chemistry; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000235:genetics; D015398:Signal Transduction; D012880:Skin Pigmentation; D014466:Ultraviolet Rays; D015854:Up-Regulation
chemical_list: D008543:Melanins; D009711:Nucleotides; D034741:RNA, Small Interfering; D044102:Receptor, Melanocortin, Type 1; D012694:Serine; D007980:Levodopa; D000242:Cyclic AMP; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: ATR; DNA repair; UV; melanin; melanocortin 1 receptor; microphthalmia