p53 promotes cell survival due to the reversibility of its cell-cycle checkpoints

Dana J. Lukin, Luis A. Carvajal, Wen Jun Liu, Lois Resnick-Silverman, James J. Manfredi

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The tumor suppressor p53 (TP53) has a well-studied role in triggering cell-cycle checkpoint in response to DNA damage. Previous studies have suggested that functional p53 enhances chemosensitivity. In contrast, data are presented to show that p53 can be required for cell survival following DNA damage due to activation of reversible cell-cycle checkpoints. The cellular outcome to DNA damage is determined by the duration and extent of the stimulus in a p53-dependent manner. In response to transient or low levels of DNA damage, p53 triggers a reversible G2 arrest, whereas a sustained p53-dependent cell-cycle arrest and senescence follows prolonged or high levels of DNA damage. Regardless of the length of treatment, p53-null cells arrest in G2, but ultimately adapt and proceed intomitosis. Interestingly, they fail to undergo cytokinesis, become multinucleated, and then die from apoptosis. Upon transient treatment with DNA-damaging agents, wild-type p53 cells reversibly arrest and repair the damage, whereas p53-null cells fail to do so and die. These data indicate that p53 can promote cell survival by inducing reversible cell-cycle arrest, thereby allowing for DNA repair. Thus, transient treatments may exploit differences between wild-type p53 and p53-null cells. Implications: Although p53 status has been suggested as a clinical predictor of chemotherapeutic efficacy, studies to date have not always supported this. This study demonstrates that p53 is still an important determinant of cell fate in response to chemotherapy, under the appropriate treatment conditions.

Original languageEnglish (US)
Pages (from-to)16-28
Number of pages13
JournalMolecular Cancer Research
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Lukin, D. J., Carvajal, L. A., Liu, W. J., Resnick-Silverman, L., & Manfredi, J. J. (2015). p53 promotes cell survival due to the reversibility of its cell-cycle checkpoints. Molecular Cancer Research, 13(1), 16-28. https://doi.org/10.1158/1541-7786.MCR-14-0177