A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest

Cell Rep. 2020 Aug 4;32(5):107995. doi: 10.1016/j.celrep.2020.107995.

Abstract

Cellular responses to stimuli can evolve over time, resulting in distinct early and late phases in response to a single signal. DNA damage induces a complex response that is largely orchestrated by the transcription factor p53, whose dynamics influence whether a damaged cell will arrest and repair the damage or will initiate cell death. How p53 responses and cellular outcomes evolve in the presence of continuous DNA damage remains unknown. Here, we have found that a subset of cells switches from oscillating to sustained p53 dynamics several days after undergoing damage. The switch results from cell cycle progression in the presence of damaged DNA, which activates the caspase-2-PIDDosome, a complex that stabilizes p53 by inactivating its negative regulator MDM2. This work defines a molecular pathway that is activated if the canonical checkpoints fail to halt mitosis in the presence of damaged DNA.

Keywords: DNA damage; PIDDosome; Pidd1; caspase-2; dynamics; imaging; p53; single-cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Caspase 2 / metabolism
  • Cell Cycle Checkpoints*
  • DNA Breaks, Double-Stranded*
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Humans
  • MCF-7 Cells
  • Mitosis
  • Models, Biological
  • Proteolysis
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Ultraviolet Rays

Substances

  • Death Domain Receptor Signaling Adaptor Proteins
  • PIDD1 protein, human
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • Caspase 2