Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells
Our results suggest that under certain conditions, p53 oscillations may act as a mechanism to suppress p53 induction, thereby restraining its pro-apoptotic activities and promoting cell-cycle arrest that allows DNA-damage repair
Our data point to the bimodal switch of p53 dynamics as a crucial control over cell fate in response to variable DNA damage, and suggest that p53 oscillations probably function as a suppressor through maintaining a low induction level of p53, which suppresses its pro-apoptotic activities and renders cell-cycle arrest that allows repair at the time of low DNA damage
Summary
The p53 pathway is differentially activated in response to distinct DNA damage, leading to alternative phenotypic outcomes in mammalian cells. 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]. Our results showed that p53 dynamics exhibit ‘switch-like’ behavior, changing from oscillatory dynamics at low damage to monotonic increase at high damage This damage dose-dependent, bimodal switch of p53 dynamics was found to regulate cell fate mainly by modulating the p53 induction level and its pro-apoptotic activities as a function of DNA-damage strength. Our results suggest that under certain conditions, p53 oscillations may act as a mechanism to suppress p53 induction, thereby restraining its pro-apoptotic activities and promoting cell-cycle arrest that allows DNA-damage repair
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