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Mol Cell. 2014 Jun 19;54(6):999-1011. doi: 10.1016/j.molcel.2014.05.030.

PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage.

Author information

  • 1Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
  • 2Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
  • 3Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
  • 4Department of Pharmacology and Nutrition Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
  • 5Department of Dietetics and Human Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
  • 6Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
  • 7Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Pharmacology and Nutrition Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Dietetics and Human Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, USA. Electronic address: jdorazio@uky.edu.

Abstract

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24950377
[PubMed - in process]
PMCID:
PMC4076709
[Available on 2015/6/19]
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