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.
Document Type
Article
Publication Date
7-2017
Digital Object Identifier (DOI)
https://doi.org/10.1111/exd.13291
Funding Information
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).
Related Content
Refer to Web version on PubMed Central for supplementary material.
Repository Citation
Wolf Horrell, Erin M.; Jarrett, Stuart G.; Carter, Katharine M.; and D'Orazio, John A., "Divergence of cAMP Signalling Pathways Mediating Augmented Nucleotide Excision Repair and Pigment Induction in Melanocytes" (2017). Markey Cancer Center Faculty Publications. 138.
https://uknowledge.uky.edu/markey_facpub/138
Supp Fig 1
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Notes/Citation Information
Published in Experimental Dermatology, v. 26, issue 7, p. 577-584.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
The copyright holder has granted the permission for posting the article here.
This is the peer reviewed version of the following article: Wolf Horrell, E. M., Jarrett, S. G., Carter, K. M., & D'Orazio, J. A. (2017). Divergence of cAMP signalling pathways mediating augmented nucleotide excision repair and pigment induction in melanocytes. Experimental Dermatology, 26(7), 577-584, which has been published in final form at https://doi.org/10.1111/exd.13291. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.