The birhythmicity increases the diversity of p53 oscillation induced by DNA damage**Project supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant Nos. 16KJB180007 and 16KJB140014), the Special Foundation of Theoretical Physics Research Program of China (Grant No. 11547025), and the National Natural Science Foundation of China (Grant No. 11574139).

Abstract

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.