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.
|Number of pages||8|
|State||Published - Jul 2017|
Bibliographical noteFunding Information:
All authors substantially contributed to experimental design, acquisition and/or interpretation of the data. EMWH and JAD designed the study. EMWH and SGJ performed the research and analysed the data. EMWH and JAD wrote drafts and critical revisions of the manuscript. Each author approved the submitted and final versions of the manuscript. We are grateful for support from the National Cancer Institute (R01 CA131075), the Melanoma Research Alliance (MRA) and the Regina Drury Endowment for Pediatric Research. We also acknowledge support by the NCI Cancer Center Support Grant (P30 CA177558) and Cancer Training Grant (T32 CA165990).
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
- DNA repair
- melanocortin 1 receptor
ASJC Scopus subject areas
- Molecular Biology