Rucaparib Treatment Alters p53 Oscillations in Single Cells to Enhance DNA-Double-Strand-Break-Induced Cell Cycle Arrest

Ryan L. Hanson, Eric Batchelor

Research output: Contribution to journalArticlepeer-review

Abstract

DNA double strand breaks induce oscillatory expression of the transcription factor p53 that is dependent on ataxia telangiectasia mutated (ATM) activity and the rate of double strand break resolution. Although p53 dynamics are known to play a role in the regulation of cell fate determination, the consequences of the variability in dynamics associated with differences in repair rates and utilized repair pathways are unknown. Using single-cell time-lapse microscopy, we found that disruption of specific repair pathways has distinct impacts on p53 dynamics. The small-molecule rucaparib, an inhibitor of the alternative end-joining-associated protein poly (ADP-ribose) polymerase (PARP), increased p53 pulse duration, altering the temporal expression of multiple p53 target genes. As a result, combination treatments of the radiomimetic drug neocarzinostatin with rucaparib drove prolonged growth arrest beyond that of DNA damage alone. This study highlights how pharmacological manipulation of DNA repair pathways may be used to alter p53 dynamics to enhance therapeutic regimens.

Original languageEnglish (US)
Article number108240
JournalCell reports
Volume33
Issue number2
DOIs
StatePublished - Oct 13 2020

Bibliographical note

Funding Information:
We thank members of the Batchelor lab, as well as D. Levens and the members of the Levens lab for helpful discussions. We also thank K. Wolcott and the NCI Flow Cytometry Core Facility for help with flow cytometry. E.B. acknowledges support for this work from the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health ( ZIA BC011382 ) and funds from the University of Minnesota .

Publisher Copyright:
© 2020 The Authors

Keywords

  • DNA damage
  • DNA repair
  • PARP
  • dynamics
  • p53
  • single cell

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

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