The birhythmicity increases the diversity of p53 oscillation induced by DNA damage

The tumor suppressor p53 mediates the cellular response to various stresses. It was experimentally shown that the concentration of p53 can show oscillations with short or long periods upon DNA damage. The underlying mechanism for this phenomenon is still not fully understood. Here, we construct a network model comprising the ATM-p53-Wip1 and p53-Mdm2 negative feedback loops and ATM autoactivation. We recapitulate the typical features of p53 oscillations including p53 birhythmicity. We show the dependence of p53 birhythmicity on various factors such as the phosphorylation status of ATM. We also perform stochastic simulation and find the noise-induced transitions between two modes of p53 oscillation,which increases the p53 variability in both the amplitude and period. These results suggest that p53 birhythmicity enhances the responsiveness of p53 network, which may facilitate its tumor suppressive function.