Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death.
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.
Tian
Bo
B
Department of Pharmacology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Yang
Qian
Q
Mao
Zixu
Z
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D051360:Cyclin-Dependent Kinase 5; D004268:DNA-Binding Proteins; D006657:Histones; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C533952:Bbc3 protein, rat; C576325:Atm protein, mouse; C495907:Cdk5 protein, rat; C475961:gamma-H2AX protein, mouse