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

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.