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

Published: 18-03-2019| Version 1 | DOI: 10.17632/zsd79s262s.1
Alexander Loewer


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.