title: p53 Promotes cell survival due to the reversibility of its cell-cycle checkpoints.
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 into mitosis. 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Lukin
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Carvajal
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Wen-jun
authors.initials: WJ
authors.lastname: Liu
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Lois
authors.initials: L
authors.lastname: Resnick-Silverman
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. james.manfredi@mssm.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Manfredi
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53