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


  • C. Sheng
  • I.H. Mendler
  • S. Rieke
  • P. Snyder
  • M. Jentsch
  • D. Friedrich
  • B. Drossel
  • A. Loewer


  • Cell Reports


  • Cell Rep 27 (1): 48-58


  • 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.