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

Summary: 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. : Combining live-cell microscopy of endogenous fluorescent reporters with computational analysis, Sheng et al. investigate how the p53-mediated response to ionizing radiation is adjusted to cellular states. They demonstrate that heterogeneous p21 dynamics post damage are caused by S phase-specific degradation through PCNA-CRL4cdt2, which is necessary for maintaining genome stability. Keywords: p53 signaling, cell cycle regulation, single-cell analysis, cellular heterogeneity, mathematical modeling, shape-based clustering, p21, PCNA, genome engineering, time-lapse microscop