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PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage.

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.

SUBMITTER: Jarrett SG 

PROVIDER: S-EPMC4076709 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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RETRACTED: PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage.

Jarrett Stuart G SG   Horrell Erin M Wolf EMW   Christian Perry A PA   Vanover Jillian C JC   Boulanger Mary C MC   Zou Yue Y   D'Orazio John A JA  

Molecular cell 20140601 6

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. An investigation by the University of Kentucky (UK) recently determined that it contains fabricated and/or falsified data committed by the lead author on the paper. The results of the investigation can be viewed at https://ori.hhs.gov/content/case-summary-jarrett-stuart-g. UK id  ...[more]

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