DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control
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RESEARCH ARTICLE
Open Access
DNA damage strength modulates a bimodal switch of p53 dynamics for cell-fate control Xi Chen1, Jia Chen2, Siting Gan2, Huaji Guan1, Yuan Zhou1, Qi Ouyang2* and Jue Shi1*
Abstract Background: The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. Recent evidence suggests that p53 expression dynamics play an important role in the differential regulation of cell fate, but questions remain as to how p53 dynamics and the subsequent cellular response are modulated by variable DNA damage. Results: We identified a novel, bimodal switch of p53 dynamics modulated by DNA-damage strength that is crucial for cell-fate control. After low DNA damage, p53 underwent periodic pulsing and cells entered cell-cycle arrest. After high DNA damage, p53 underwent a strong monotonic increase and cells activated apoptosis. We found that the damage dose-dependent bimodal switch was due to differential Mdm2 upregulation, which controlled the alternative cell fates mainly by modulating the induction level and pro-apoptotic activities of p53. Conclusions: Our findings not only uncover a new mode of regulation for p53 dynamics and cell fate, but also suggest that p53 oscillation may function as a suppressor, maintaining a low level of p53 induction and pro-apoptotic activities so as to render cell-cycle arrest that allows damage repair.
Background An efficient and precisely controlled DNA-damage response is crucial for cell survival. In mammalian cells, the p53 regulatory pathway, consisting mainly of the tumor suppressor protein p53 and its downstream transcriptional targets, plays an essential role in mediating this crucial stress response to chromosomal damage [1-3]. Depending on the type and severity of DNA damage, the p53 pathway activates either cell-cycle arrest that allows repair of the damage or alternatively, death of the cell through apoptosis, but the mechanism by which variation in DNA-damage strength differentially regulates p53 pathway dynamics, and the effect that this has on cell fate, are poorly understood. Mild DNA damage generally induces a moderate increase in p53 level, and results in transient cell-cycle arrest that allows damage repair, whereas severe and possibly irreparable DNA damage leads to a large increase in p53, followed by cell death [4]. DNA damage is * Correspondence: [email protected]; [email protected] 2 Center for Quantitative Biology and State Key Laboratory for Mesoscopic Physics, Peking University, 100871, Beijing, P. R. China 1 Center for Quantitative Systems Biology and Department of Physics, Hong Kong Baptist University, 224 Waterloo Road, Kowloon Tong, Kowloon, Hong Kong, China
known to upregulate p53 by attenuating its interaction with Mdm2, the E3 ubiquitin ligase that targets p53 for proteasome-mediated degradation [5,6]. Less clear is how the severity of DNA damage modulates the degree of attenuation in p53-Mdm2 interactions, giving rise to differential p53 expression that results in
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