Blunted melanocortin 1 receptor (MC1R) signaling promotes melanocyte genomic instability in part by attenuating cAMP-mediated DNA repair responses, particularly nucleotide excision repair (NER), which recognizes and clears mutagenic photodamage. cAMP-enhanced NER is mediated by interactions between the ataxia telangiectasia-mutated and Rad3-related (ATR) and xeroderma pigmentosum complementation group A (XPA) proteins. We now report a critical role for sirtuin 1 (SIRT1) in regulating ATR-mediated phosphorylation of XPA. SIRT1 deacetylates XPA at residues Lys-63, Lys-67, and Lys-215 to promote interactions with ATR. Mutant XPA containing acetylation mimetics at residues Lys-63, Lys-67, and Lys-215 exhibit blunted UV-dependent ATR–XPA interactions even in the presence of cAMP signals. ATR-mediated phosphorylation of XPA on Ser-196 enhances cAMP-mediated optimization of NER and is promoted by SIRT1-mediated deacetylation of XPA on Lys-63, Lys-67, and Lys-215. Interference with ATR-mediated XPA phosphorylation at Ser-196 by persistent acetylation of XPA at Lys-63, Lys-67, and Lys-215 delays repair of UV-induced DNA damage and attenuates cAMP-enhanced NER. Our study identifies a regulatory ATR–SIRT1–XPA axis in cAMP-mediated regulation melanocyte genomic stability, involving SIRT1-mediated deacetylation (Lys-63, Lys-67, and Lys-215) and ATR-dependent phosphorylation (Ser-196) post-translational modifications of the core NER factor XPA.
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This work was supported by National Institutes of Health Grants R01CA131075, P30 CA177558, and T32 CA165990, the Melanoma Research Alliance, the Regina Drury Pediatric Research Endowed Chair Fund, the DanceBlue Golden Matrix Fund, and the Markey Cancer Foundation.
We acknowledge the imaging core of the University of Kentucky Center for Cancer and Metabolism COBRE Grant P20 GM121327 from the National Institutes of Health and the Biostatistics and Bioinformatics Shared Resource Facility of the Markey Cancer Center.
This article contains Figs. S1–S12.
Jarrett, Stuart G.; Carter, Katharine M.; Bautista, Robert-Marlo; He, Daheng; Wang, Chi; and D’Orazio, John A., "Sirtuin 1-Mediated Deacetylation of XPA DNA Repair Protein Enhances Its Interaction with ATR Protein and Promotes cAMP-Induced DNA Repair of UV Damage" (2018). Markey Cancer Center Faculty Publications. 116.