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

研究成果: Article査読

16 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1015-1029
ページ数15
ジャーナルCell Cycle
13
6
DOI
出版ステータスPublished - 15-03-2014
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 発生生物学
  • 細胞生物学

フィンガープリント

「Wild-type p53-induced phosphatase 1 (Wip1) forestalls cellular premature senescence at physiological oxygen levels by regulating DNA damage response signaling during DNA replication」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル