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

Nature Cell Biology volume 11, pages 211–218 (2009)Cite this article

A Corrigendum to this article was published on 01 August 2009

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.

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Figure 1: Cdk5 directly phosphorylates ATM in vitro and in cells.
Figure 2: Activation of Cdk5 by calpain contributes to ATM activation induced by DNA damage.
Figure 3: Inhibition of Cdk5 blocks DNA-damage-induced phosphorylation and activation of ATM and its effects on downstream targets.
Figure 4: Cdk5 regulates CPT-induced cell-cycle re-entry of post-mitotic neurons.
Figure 5: The Cdk5–ATM signal regulates neuronal death induced by DNA damage.

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Acknowledgements

We thank Bert Vogelstein, Richard Gatti, Michael Kastan, Martin Lavin and Shuki Mizutani for p53 reporter constructs, purified ATM protein, ATM mammalian expression constructs, GST–ATM expression constructs, and A-T cell lines, respectively. 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.).

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Authors and Affiliations

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

    Bo Tian, Qian Yang & Zixu Mao

  2. Center for Neurodegenerative Disease, Emory University School of Medicine, 615 Michael Street, Atlanta, 30322, GA, USA

    Bo Tian, Qian Yang & Zixu Mao

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  1. Bo Tian
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  2. Qian Yang
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Contributions

Z.M. coordinated the overall project and planned the original experimental design; B.T. and Q.Y. conducted the experiments; Z.M. and B.T. analysed the data and wrote the paper.

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Correspondence to Zixu Mao.

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The authors declare no competing financial interests.

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Tian, B., Yang, Q. & Mao, Z. Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death. Nat Cell Biol 11, 211–218 (2009). https://doi.org/10.1038/ncb1829

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