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

Michael Tsabar; Caroline S. Mock; Veena Venkatachalam; Jose Reyes; Kyle W. Karhohs; Trudy G. Oliver; Aviv Regev; Ashwini Jambhekar; Galit Lahav

Cell Reports (Aug 2020)

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

Michael Tsabar,
Caroline S. Mock,
Veena Venkatachalam,
Jose Reyes,
Kyle W. Karhohs,
Trudy G. Oliver,
Aviv Regev,
Ashwini Jambhekar,
Galit Lahav

Affiliations

Michael Tsabar: 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
Caroline S. Mock: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Veena Venkatachalam: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA 02115, USA
Jose Reyes: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Kyle W. Karhohs: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Trudy G. Oliver: Huntsman Cancer Institute at University of Utah, Salt Lake City, UT 84112, USA
Aviv Regev: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Ashwini Jambhekar: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Galit Lahav: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Corresponding author

Journal volume & issue: Vol. 32, no. 5
p. 107995

Abstract

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Summary: 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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