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

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

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 ; Mendler, Isabella-Hilda ; Rieke, Sara ; Snyder, Petra ; Jentsch, Marc ; Friedrich, Dhana ; Drossel, Barbara ; Loewer, Alexander
Type of entry: Bibliographie
Title: PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells
Language: English
Date: 2 April 2019
Journal or Publication Title: Cell Reports
Volume of the journal: 27
Issue Number: 1
DOI: 10.1016/j.celrep.2019.03.031
URL / URN: https://doi.org/10.1016/j.celrep.2019.03.031
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.

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 (2021 merged in Institute for Condensed Matter Physics)
05 Department of Physics > Institute for condensed matter physics (2021 merged in Institute for Condensed Matter Physics) > Statistische Physik und komplexe Systeme
Date Deposited: 15 Apr 2019 09:33
Last Modified: 15 Apr 2019 09:33
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