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Nat Cell Biol. 2009 Feb;11(2):211-8. doi: 10.1038/ncb1829. Epub 2009 Jan 18.

Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death.

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1
Department of Pharmacology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.

Erratum in

  • Nat Cell Biol. 2009 Aug;11(8);1042.

Abstract

The phosphatidylinositol-3-kinase-like kinase ATM (ataxia-telangiectasia mutated) has a central role in coordinating DNA damage responses, including cell-cycle checkpoint control, DNA repair and apoptosis. Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition. However, the mechanism by which DNA damage activates ATM is poorly understood. Here we show that Cdk5 (cyclin-dependent kinase 5), activated by DNA damage, directly phosphorylates ATM at Ser 794 in post-mitotic neurons. Phosphorylation at Ser 794 precedes, and is required for, ATM autophosphorylation at Ser 1981, and activates ATM kinase activity. The Cdk5-ATM signal regulates phosphorylation and function of the ATM targets p53 and H2AX. Interruption of the Cdk5-ATM pathway attenuates DNA-damage-induced neuronal cell cycle re-entry and expression of the p53 targets PUMA and Bax, protecting neurons from death. Thus, activation of Cdk5 by DNA damage serves as a critical signal to initiate the ATM response and regulate ATM-dependent cellular processes.

PMID:
19151707
PMCID:
PMC2760486
DOI:
10.1038/ncb1829
[Indexed for MEDLINE]
Free PMC Article

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