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AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

Jarrett, Stuart G ; Wolf Horrell, Erin M ; D'Orazio, John A

Nucleic acids research, 2016-12, Vol.44 (22), p.10711-10726 [Periódico revisado por pares]

England: Oxford University Press

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Título:
AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair
Autor: Jarrett, Stuart G ; Wolf Horrell, Erin M ; D'Orazio, John A
Assuntos: A Kinase Anchor Proteins - physiology ; Ataxia Telangiectasia Mutated Proteins - metabolism ; Cell Cycle Proteins - physiology ; Cyclic AMP-Dependent Protein Kinases - physiology ; DNA Damage ; DNA Repair ; Genome Integrity, Repair and ; HEK293 Cells ; Humans ; Kinetics ; Mutagenesis ; Phosphorylation ; Protein Processing, Post-Translational ; Protein Transport ; Xeroderma Pigmentosum Group A Protein - metabolism
É parte de: Nucleic acids research, 2016-12, Vol.44 (22), p.10711-10726
Descrição: Loss-of-function in melanocortin 1 receptor (MC1R), a G protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12-ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5' strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12-ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.
Editor: England: Oxford University Press
Idioma: Inglês

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AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair

Jarrett, Stuart G ; Wolf Horrell, Erin M ; D'Orazio, John A

England: Oxford University Press

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