AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

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 amajor inheritedmelanoma 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 telangiectasiamutated and Rad3-related (ATR) at S435, a post-Translational event required for cAMPenhanced 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 ATRpS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UVinduced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKAmediated ATR phosphorylation, and identify a repair complex consisting of AKAP12-ATR-pS435-XPA at photodamage,which is essential for cAMP-enhanced NER.