Abstract

Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5΄ strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12–ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.

Document Type

Article

Publication Date

12-15-2016

Notes/Citation Information

Published in Nucleic Acids Research, v. 44, issue 22, p. 10711-10726.

© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Digital Object Identifier (DOI)

https://doi.org/10.1093/nar/gkw871

Funding Information

National Institutes of Health [R01CA131075, T32CA165990]; Markey Cancer Center's National Cancer Institute Cancer Center Support Grant [P30CA177558]; Melanoma Research Alliance; Drury Pediatric Research Endowed Chair Fund; Markey Cancer Foundation; Jennifer and David Dickens Melanoma Research Foundation. Funding for open access charge: National Cancer Institute.

Related Content

Supplementary Data are available at NAR Online.

gkw871_Supp.pdf (14651 kB)
Supplementary Data: Supplemental Figure Legends

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