PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage
| Autor: | Stuart G, Jarrett, Erin M Wolf, Horrell, Perry A, Christian, Jillian C, Vanover, Mary C, Boulanger, Yue, Zou, John A, D'Orazio |
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| Rok vydání: | 2013 |
| Předmět: |
DNA Repair
Pigmentation Ultraviolet Rays Ataxia Telangiectasia Mutated Proteins Cyclic AMP-Dependent Protein Kinases Article Xeroderma Pigmentosum Group A Protein DNA-Binding Proteins Mice Inbred C57BL Mice HEK293 Cells Mutagenesis Cell Line Tumor MCF-7 Cells Animals Humans RNA Interference Phosphorylation RNA Small Interfering Protein Processing Post-Translational Receptor Melanocortin Type 1 DNA Damage Signal Transduction |
| Zdroj: | Mol Cell |
| ISSN: | 1097-4164 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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