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

Bo Tian1, Qian Yang, Zixu Mao

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

Nature Cell Biology
|January 20, 2009
PubMed

Insights

DNA damage activates ataxia-telangiectasia mutated (ATM) kinase through cyclin-dependent kinase 5 (Cdk5) phosphorylation. This Cdk5-ATM pathway is crucial for neuronal survival and DNA damage response, protecting neurons from death.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Neuroscience

Background:

  • The ataxia-telangiectasia mutated (ATM) kinase is vital for DNA damage response, regulating cell-cycle checkpoints, DNA repair, and apoptosis.
  • ATM mutations are linked to neurodegeneration and cancer, but its activation mechanism by DNA damage remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of ATM activation by DNA damage in post-mitotic neurons.
  • To investigate the role of cyclin-dependent kinase 5 (Cdk5) in initiating the ATM-mediated DNA damage response.

Main Methods:

  • Investigated the direct phosphorylation of ATM by Cdk5 at Serine 794 in response to DNA damage.
  • Analyzed the impact of Cdk5-mediated ATM phosphorylation on ATM autophosphorylation at Serine 1981 and kinase activity.
  • Examined the regulation of ATM targets, including p53 and H2AX, by the Cdk5-ATM signaling axis.
  • Assessed the effect of interrupting the Cdk5-ATM pathway on neuronal cell cycle re-entry and apoptosis-related gene expression.

Main Results:

  • DNA damage activates Cdk5, which directly phosphorylates ATM at Ser 794 in post-mitotic neurons.
  • Phosphorylation of ATM at Ser 794 by Cdk5 is a prerequisite for ATM autophosphorylation at Ser 1981 and subsequent kinase activation.
  • The Cdk5-ATM pathway modulates the phosphorylation and function of ATM targets p53 and H2AX.
  • Disruption of the Cdk5-ATM pathway inhibits DNA-damage-induced neuronal cell cycle re-entry and the expression of pro-apoptotic factors PUMA and Bax, thereby conferring neuroprotection.

Conclusions:

  • Cdk5 activation by DNA damage acts as a critical upstream signal initiating the ATM response in neurons.
  • The Cdk5-ATM signaling cascade is essential for regulating ATM-dependent cellular processes and ensuring neuronal survival following DNA damage.

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