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.
Digital Object Identifier (DOI)
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.
Supplementary Data are available at NAR Online.
Jarrett, Stuart G.; Horrell, Erin M. Wolf; and D'Orazio, John A., "AKAP12 Mediates PKA-Induced Phosphorylation of ATR to Enhance Nucleotide Excision Repair" (2016). Markey Cancer Center Faculty Publications. 73.