Transient Activation of p53 in G2 Phase Is Sufficient to Induce Senescence

• DNA damage can result in a transient cell-cycle arrest or permanent cell-cycle exit
• DNA damage causes nuclear retention of Cyclin B1 followed by activation of APC/CCdh1
• DNA-damage-induced nuclear Cyclin B1-Cdk1 is refractory to activation
• Transient activation of p53 in G2 phase is sufficient to induce senescence

SummaryDNA damage can result in a transient cell-cycle arrest or lead to permanent cell-cycle withdrawal. Here we show that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. This permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear retention of Cyclin B1. This rapid response is followed by the activation of the APC/CCdh1 (the anaphase-promoting complex/cyclosome and its coactivator Cdh1) several hours later. Inhibition of APC/CCdh1 activity fails to prevent cell-cycle withdrawal, whereas 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 retention of Cyclin B1 as the first irreversible step in the onset of senescence.

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