Wild-type p53-induced phosphatase 1 (Wip1) forestalls cellular premature senescence at physiological oxygen levels by regulating DNA damage response signaling during DNA replication

Hiroyasu Sakai, Hidetsugu Fujigaki, Sharlyn J. Mazur, Ettore Appella

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Wip1 (protein phosphatase Mg2+/Mn2+-dependent 1D, Ppm1d) is a nuclear serine/threonine protein phosphatase that is induced by p53 following the activation of DNA damage response (DDR) signaling. Ppm1d -/- mouse embryonic fibroblasts (MEFs) exhibit premature senescence under conventional culture conditions; however, little is known regarding the role of Wip1 in regulating cellular senescence. In this study, we found that even at a representative physiological concentration of 3% O2, Ppm1d-/- MEFs underwent premature cellular senescence that depended on the functional activation of p53. Interestingly, Ppm1d-/- MEFs showed increased H2AX phosphorylation levels without increased levels of reactive oxygen species (ROS) or DNA base damage compared with wild-type (Wt) MEFs, suggesting a decreased threshold for DDR activation or sustained DDR activation during recovery. Notably, the increased H2AX phosphorylation levels observed in Ppm1d-/- MEFs were primarily associated with S-phase cells and predominantly dependent on the activation of ATM. Moreover, these same phenotypes were observed when Wt and Ppm1d-/- MEFs were either transiently or chronically exposed to low levels of agents that induce replication-mediated double-stranded breaks. These findings suggest that Wip1 prevents the induction of cellular senescence at physiological oxygen levels by attenuating DDR signaling in response to endogenous double-stranded breaks that form during DNA replication.

Original languageEnglish
Pages (from-to)1015-1029
Number of pages15
JournalCell Cycle
Volume13
Issue number6
DOIs
Publication statusPublished - 15-03-2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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