p53 dynamics in single cells are temperature-sensitive

Abstract

Cells need to preserve genome integrity despite varying cellular and physical states. p53, the guardian of the genome, plays a crucial role in the cellular response to DNA damage by triggering cell cycle arrest, apoptosis or senescence. Mutations in p53 or alterations in its regulatory network are major driving forces in tumorigenesis. As multiple studies indicate beneficial effects for hyperthermic treatments during radiation-or chemotherapy of human cancers, we aimed to understand how p53 dynamics after genotoxic stress are modulated by changes in temperature across a physiological relevant range. To this end, we employed a combination of time-resolved live-cell microscopy and computational analysis techniques to characterise the p53 response in thousands of individual cells. Our results demonstrate that p53 dynamics upon ionizing radiation are temperature dependent. In the range of 33 °C to 39 °C, pulsatile p53 dynamics are modulated in their frequency. Above 40 °C, which corresponds to mild hyperthermia in a clinical setting, we observed a reversible phase transition towards sustained hyperaccumulation of p53 disrupting its canonical response to DNA double strand breaks. Moreover, we provide evidence that mild hyperthermia alone is sufficient to induce a p53 response in the absence of genotoxic stress. These insights highlight how the p53-mediated DNA damage response is affected by alterations in the physical state of a cell and how this can be exploited by appropriate timing of combination therapies to increase the efficiency of cancer treatments.

Temperature Modulation of the DBDp53 Structure as Monitored by Static and Time-Resolved Fluorescence Combined with Molecular Dynamics Simulations

“…This could affect the capability of p53 to bind different ligands and, more generally, the p53 functionality. In this respect, it has been recently observed that a change in p53 dynamics with temperature from 33 to 39 °C is related to the increased capability of the cell to preserve the genetic integrity …”

“…In this respect, it has been recently observed that a change in p53 dynamics with temperature from 33 to 39 °C is related to the increased capability of the cell to preserve the genetic integrity. 51 MD Simulation Results. To get further information about the effects of temperature on the structure and dynamics of DBD, with particular attention to the Trp146 environment, we have performed MD simulations of DBD in water.…”

Microwave hyperthermia represses human papillomavirus oncoprotein activity and induces cell death due to cell stress in 3D tissue models of anogenital precancers and cancers

“… 25 , 33 Cellular heat shock increases expression of p53 and leads to its phosphorylation and subsequent tetramer formation in the nucleus. This results in stabilisation of p53 39 , 40 , 41 , 42 which can then activate transcription of HSP70, leading to the heat shock response and apoptosis. 43 Our data suggest a heat-shock-induced reduction in E6 protein levels, which should add to the increased p53 levels due to hyperthermia.…”

Accurate Three-Dimensional Thermal Dosimetry and Assessment of Physiologic Response Are Essential for Optimizing Thermoradiotherapy

“…This switch would reduce oxygen consumption rate, thereby contributing to reoxygenation. (2) Mild temperature heating has been reported to induce apoptosis and/or senescence in some tumor cell types in vitro and in vivo [ 145 , 146 ]. The induction of apoptosis and senescence would reduce oxygen consumption rate.…”