Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 19025-19037 |
| Number of pages | 13 |
| Journal | Journal of Biological Chemistry |
| Volume | 293 |
| Issue number | 49 |
| DOIs | |
| State | Published - Dec 7 2018 |
Bibliographical note
Publisher Copyright:© 2018 Jarrett et al.
Funding
Acknowledgments—We are grateful to Anand Ganesan for providing the ATR–P224L construct and to David Cortez for the generous gift of HCT116 cells. 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 work was supported by National Institutes of Health Grants R01 CA131075, 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. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
| Funders | Funder number |
|---|---|
| The Markey Biostatistics and Bioinformatics Shared Resource Facility | |
| DanceBlue Golden Matrix Fund | |
| Markey Cancer Center | |
| Markey Cancer Center Foundation | |
| NIH-funded University of Kentucky Center for Cancer and Metabolism | P20 GM121327 |
| National Institutes of Health (NIH) | P30 CA177558, T32 CA165990 |
| National Childhood Cancer Registry – National Cancer Institute | R01CA131075 |
| Melanoma Research Alliance Foundation |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology