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

• Type of Material: Article
• Authors: Bo Tian, Emory University; Qian Yang, Emory University; Zixu Mao, Emory University
• Language: English
• Date: 2009-02
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009, Rights Managed by Nature Publishing Group
• Final Published Version (URL): http://www.nature.com/ncb/journal/v11/n2/full/ncb1829.html
• Title of Journal or Parent Work: Nature Cell Biology
• ISSN: 1465-7392
• Volume: 11
• Issue: 2
• Start Page: 211
• End Page: 218
• Grant/Funding Information: This work was partially supported by NIH grants R01 NS048254 (Z. M.) and R01 AG023695 (Z. M.) and The Robert W. Woodruff Health Sciences Center Fund (Z. M.).
• Research Categories: Biology, Cell; Health Sciences, Pharmacology

Abstract

The phosphatidylinositol-3-kinase-like kinase ATM (Ataxia – telangiectasia mutated) plays a central role in coordinating the 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. We show that Cdk5 (cyclin-dependent kinase 5), activated by DNA damage, directly phosphorylates ATM at serine 794 in postmitotic neurons. Phosphorylation at serine 794 precedes and is required for ATM autophosphorylation at serine 1981, and activates ATM kinase activity. Cdk5-ATM signal regulates phosphorylation and function of ATM targets p53 and H2AX. Interruption of Cdk5-ATM pathway attenuates DNA damage-induced neuronal cell cycle reentry and expression of p53 targets PUMA and Bax, protecting neurons from DNA damage-induced death. Thus, activation of Cdk5 by DNA damage serves as a critical signal to initiate ATM response and regulate ATM-dependent cellular processes.