A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest
Name
1-s2.0-S2211124720309803-main.pdf
Description
Published version
Size
3.45 MB
Format
Adobe PDF
Checksum (MD5)
88f2b36ffff1fc9301bae90448b82ba5
Author(s)
Tsabar, Michael
Mock, Caroline S
Venkatachalam, Veena
Reyes, Jose
Karhohs, Kyle W
Oliver, Trudy G
Regev, Aviv
Jambhekar, Ashwini
Lahav, Galit
Date Issued
2020
Journal
Cell Reports
Publisher
Elsevier BV
Version
Final published version
Abstract
© 2020 The Author(s) 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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CELREP.2020.107995
