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p53 dynamics in single cells are temperature-sensitive

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 m...

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Autores principales: Jentsch, Marcel, Snyder, Petra, Sheng, Caibin, Cristiano, Elena, Loewer, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992775/
https://www.ncbi.nlm.nih.gov/pubmed/32001771
http://dx.doi.org/10.1038/s41598-020-58267-1
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author Jentsch, Marcel
Snyder, Petra
Sheng, Caibin
Cristiano, Elena
Loewer, Alexander
author_facet Jentsch, Marcel
Snyder, Petra
Sheng, Caibin
Cristiano, Elena
Loewer, Alexander
author_sort Jentsch, Marcel
collection PubMed
description 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.
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spelling pubmed-69927752020-02-05 p53 dynamics in single cells are temperature-sensitive Jentsch, Marcel Snyder, Petra Sheng, Caibin Cristiano, Elena Loewer, Alexander Sci Rep Article 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. Nature Publishing Group UK 2020-01-30 /pmc/articles/PMC6992775/ /pubmed/32001771 http://dx.doi.org/10.1038/s41598-020-58267-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Jentsch, Marcel
Snyder, Petra
Sheng, Caibin
Cristiano, Elena
Loewer, Alexander
p53 dynamics in single cells are temperature-sensitive
title p53 dynamics in single cells are temperature-sensitive
title_full p53 dynamics in single cells are temperature-sensitive
title_fullStr p53 dynamics in single cells are temperature-sensitive
title_full_unstemmed p53 dynamics in single cells are temperature-sensitive
title_short p53 dynamics in single cells are temperature-sensitive
title_sort p53 dynamics in single cells are temperature-sensitive
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992775/
https://www.ncbi.nlm.nih.gov/pubmed/32001771
http://dx.doi.org/10.1038/s41598-020-58267-1
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