2. Academic Validation
  3. A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest

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.
Michael Tsabar 1,  Caroline S Mock 2,  Veena Venkatachalam 3,  Jose Reyes 2,  Kyle W Karhohs 2,  Trudy G Oliver 4,  Aviv Regev 5,  Ashwini Jambhekar 2,  Galit Lahav 6
Affiliations

Affiliations

  • 1 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 2 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Huntsman Cancer Institute at University of Utah, Salt Lake City, UT 84112, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 6 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 32755587 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.

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