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Reversal of the ATM/ATR-mediated DNA damage response by the oncogenic phosphatase PPM1D

Xiongbin Lu1, Thuy-Ai Nguyen, Lawrence A Donehower

  • 1Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA.

Cell Cycle (Georgetown, Tex.)
|June 23, 2005
PubMed

Insights

The DNA damage response involves ATM/ATR kinases and PPM1D phosphatase. PPM1D (Wip1) reverses ATM/ATR phosphorylation, suppressing cell cycle checkpoints and DNA repair, potentially contributing to breast cancer.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Biology

Background:

  • Eukaryotic cells possess DNA damage response (DDR) pathways crucial for genomic stability and preventing cancer.
  • ATM and ATR kinases are central sensors and signal transducers in the DDR, phosphorylating key proteins.
  • PPM1D (Wip1) is a type 2C serine/threonine phosphatase that dephosphorylates DDR proteins.

Purpose of the Study:

  • To investigate the role of PPM1D (Wip1) in reversing ATM/ATR-mediated phosphorylation of p53 and Chk1.
  • To determine the impact of PPM1D activity on DNA damage-induced cell cycle checkpoints and DNA repair.
  • To explore the potential role of PPM1D in a p53 negative feedback loop and its implications in breast cancer.

Main Methods:

  • Biochemical assays to assess the phosphatase activity of PPM1D on phosphorylated p53 and Chk1.
  • Cellular assays to evaluate the effect of PPM1D on cell cycle checkpoints and DNA repair.
  • Analysis of PPM1D expression and its correlation with p53 status in human breast cancer samples.

Main Results:

  • PPM1D dephosphorylates ATM/ATR-phosphorylated p53 and Chk1, reducing their functional activity.
  • PPM1D suppresses DNA damage-induced cell cycle checkpoints and impairs DNA repair.
  • PPM1D is transcriptionally activated by p53 and inhibits p53 activity through multiple mechanisms, forming a negative feedback loop.
  • PPM1D amplification and overexpression in p53 wild-type breast cancers suggest its role in tumorigenesis.

Conclusions:

  • PPM1D acts as a critical negative regulator of the DNA damage response by reversing key phosphorylation events.
  • PPM1D's feedback inhibition of p53 and suppression of DDR pathways highlight its role in maintaining cellular homeostasis.
  • Dysregulation of PPM1D may contribute to genomic instability and cancer development, particularly in breast cancer with wild-type p53.

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