Hyperactivation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage.
A functional DNA damage response is essential for maintaining genome integrity in the presence of DNA double-strand breaks. It is mainly coordinated by the kinases ATM, ATR, and DNA-PKcs, which control the repair of broken DNA strands and relay the damage signal to the tumor suppressor p53 to induce cell cycle arrest, apoptosis, or senescence. Although many functions of the individual kinases have been identified, it remains unclear how they act in concert to ensure faithful processing of the damage signal. Using specific inhibitors and quantitative analysis at the single-cell level, we systematically characterize the contribution of each kinase for regulating p53 activity. Our results reveal a new regulatory interplay in which loss of DNA-PKcs function leads to hyperactivation of ATM and amplification of the p53 response, sensitizing cells for damage-induced senescence. This interplay determines the outcome of treatment regimens combining irradiation with DNA-PKcs inhibitors in a p53-dependent manner.
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Ana
A
Finzel
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Andrea
A
Grybowski
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Jette
J
Strasen
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Elena
E
Cristiano
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany Department of Biology, Technische Universitaet Darmstadt, 64287 Darmstadt, Germany loewer@bio.tu-darmstadt.de.
Alexander
A
Loewer
D000072283:A549 Cells; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases