Oscillatory Dynamics and Regulatory Mechanisms of the p53-Per2 Network in DNA-Damaged Cells.

Abstract

Circadian rhythm disruptions are linked to increased cancer risk and unfavorable prognosis in patients with cancer, highlighting the critical role of the interplay between the circadian rhythm factor Per2 and the tumor suppressor p53. This brief presents, for the first time, a mathematical model to capture the dynamics of the p53-Per2 network in DNA-damaged cells. The model accurately describes the different stages of the process from unstressed cells to cellular repair and finally to apoptosis as the degree of DNA damage increases. Furthermore, it is found that increasing the inhibition of Per2 by p53 leads to the phase advance of Per2 oscillations, whereas by modulating the inhibition of Mdm2 by Per2, an independent amplitude modulation of active p53 can be achieved, with the range of modulation increasing with the strength of the inhibition. Moreover, the effects of time delays inherent in the transcription, translation, and nuclear translocation of Per2 on the circadian rhythm of DNA-damaged cells are quantitatively investigated by theoretical analyses. It is found that time delays can induce stable oscillations through a supercritical Hopf bifurcation, thereby maintaining the circadian function of DNA-damaged cells and enhancing their DNA-damage repair capacity. This study proposes new insights into cancer prevention and treatment strategies.