DNA damage-induced checkpoints enforce a cell cycle arrest while the damage is being repaired. Following successful repair, the DNA damage-induced G1 and G2 checkpoints are silenced allowing resumption of the cell cycle. However, the fate of a damaged cell can differ. A cell might not recover from the DNA damaging insult and undergo a permanent cell cycle arrest, or die. How cells enforce a permanent cell cycle exit is currently unknown. Work from the Lahav lab has shown that p53-levels oscillate in response to DNA damage, and that the amount of oscillations is dependent on the amount of DNA damage. Changing the oscillatory dynamics of p53 can readily influence cell fate decisions. Indeed, other have shown that p53 can promote a permanent cell cycle arrest in response to prolonged exposure to DNA damage in G2, and is required for the induction of senescence in response to continuous stimuli such as critically short telomeres or oncogene activation.
We find that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. We demonstrate that a permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear translocation of Cyclin B1. This rapid response is followed by the activation of the APC/CCdh1 several hours later. Inhibition of APC/CCdh1 activity fails to prevent cell cycle withdrawal. In contrast, preventing nuclear retention of Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction of p53 in G2 cells is sufficient to induce senescence. Taken together, these results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear translocation of Cyclin B1 as the first irreversible step in the onset of senescence.