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PCNA-mediated degradation of p21 coordinates the DNA damage response and cell cycle regulation in individual cells

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Item Type:Article
Title:PCNA-mediated degradation of p21 coordinates the DNA damage response and cell cycle regulation in individual cells
Creators Name:Sheng, C. and Mendler, I.H. and Rieke, S. and Snyder, P. and Jentsch, M. and Friedrich, D. and Drossel, B. and Loewer, A.
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-CRL4(cdt2) 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.
Keywords:p53 Signaling, Cell Cycle Regulation, Single-Cell Analysis, Cellular Heterogeneity, Mathematical Modeling, Shape-Based Clustering, p21, PCNA, Genome Engineering, Time-Lapse Microscopy
Source:Cell Reports
ISSN:2211-1247
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:27
Number:1
Page Range:48-58
Date:2 April 2019
Official Publication:https://doi.org/10.1016/j.celrep.2019.03.031
PubMed:View item in PubMed

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