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PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells

Sheng, Caibin and Mendler, Isabella-Hilda and Rieke, Sara and Snyder, Petra and Jentsch, Marc and Friedrich, Dhana and Drossel, Barbara and Loewer, Alexander (2019):
PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells.
In: Cell Reports, pp. 47-58.e7, 27, (1), DOI: 10.1016/j.celrep.2019.03.031, [Online-Edition: https://doi.org/10.1016/j.celrep.2019.03.031],
[Article]

Abstract

To enable reliable cell fate decisions, mammalian cells need to adjust their responses to dynamically changing internal states by rewiring the corresponding signaling networks. Here, we combine time-lapse microscopy of endogenous fluorescent reporters with computational analysis to understand at the single-cell level how the p53-mediated DNA damage response is adjusted during cell cycle progression. Shape-based clustering revealed that the dynamics of the CDK inhibitor p21 diverges from the dynamics of its transcription factor p53 during S phase. Using mathematical modeling, we predict and experimentally validate that S phase-specific degradation of p21 by PCNA-CRL4cdt2 is sufficient to explain these heterogeneous responses. This highlights how signaling pathways and cell regulatory networks intertwine to adjust the cellular response to the individual needs of a given cell.

Item Type: Article
Erschienen: 2019
Creators: Sheng, Caibin and Mendler, Isabella-Hilda and Rieke, Sara and Snyder, Petra and Jentsch, Marc and Friedrich, Dhana and Drossel, Barbara and Loewer, Alexander
Title: PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells
Language: English
Abstract:

To enable reliable cell fate decisions, mammalian cells need to adjust their responses to dynamically changing internal states by rewiring the corresponding signaling networks. Here, we combine time-lapse microscopy of endogenous fluorescent reporters with computational analysis to understand at the single-cell level how the p53-mediated DNA damage response is adjusted during cell cycle progression. Shape-based clustering revealed that the dynamics of the CDK inhibitor p21 diverges from the dynamics of its transcription factor p53 during S phase. Using mathematical modeling, we predict and experimentally validate that S phase-specific degradation of p21 by PCNA-CRL4cdt2 is sufficient to explain these heterogeneous responses. This highlights how signaling pathways and cell regulatory networks intertwine to adjust the cellular response to the individual needs of a given cell.

Journal or Publication Title: Cell Reports
Volume: 27
Number: 1
Divisions: 10 Department of Biology
10 Department of Biology > Systems Biology of the Stress Response
DFG-Graduiertenkollegs
DFG-Graduiertenkollegs > Research Training Group 1657 Molecular and cellular responses to ionizing radiation
05 Department of Physics
05 Department of Physics > Institute for condensed matter physics
05 Department of Physics > Institute for condensed matter physics > Statistische Physik und komplexe Systeme
Date Deposited: 15 Apr 2019 09:33
DOI: 10.1016/j.celrep.2019.03.031
Official URL: https://doi.org/10.1016/j.celrep.2019.03.031
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