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

Stuart G. Jarrett, Erin M.Wolf Horrell, Perry A. Christian, Jillian C. Vanover, Mary C. Boulanger, Yue Zou, John A. D'Orazio

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

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.

Original languageEnglish
Pages (from-to)999-1011
Number of pages13
JournalMolecular Cell
Volume54
Issue number6
DOIs
StatePublished - Jun 19 2014

Bibliographical note

Funding Information:
We are indebted to David Fisher, Chris Paumi, Daret St.Clair, and David Cortez and for helpful comments and insight. We thank Carol Beach and Haining Zhu of the University of Kentucky Proteomics Core Facility. This work was supported by the following NIH grants: R01 CA131075, UL1TR000117, ES07266, T32 ES007266, and T32CA165990. We also thank the Drury Pediatric Research Endowed Chair Fund, Wendy Will Case Cancer Research Fund, Markey Cancer Foundation, Children’s Miracle Network, and Jennifer and David Dickens Melanoma Research Foundation.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage'. Together they form a unique fingerprint.

Cite this