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Phosphorylation of Daxx by ATM contributes to DNA damage-induced p53 activation

Jun Tang1, Trisha Agrawal, Qian Cheng

  • 1Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Plos One
|February 14, 2013
PubMed

Insights

DNA damage triggers ATM kinase to phosphorylate Daxx, disrupting the Daxx-Mdm2 interaction. This dissociation is crucial for activating the tumor suppressor p53, revealing a new regulatory step in cancer prevention.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Oncology

Background:

  • p53 is a key tumor suppressor, inducing anti-proliferative responses to cellular stress.
  • p53 activity is tightly regulated by the ubiquitin ligase Mdm2.
  • Daxx stabilizes Mdm2 and enhances its activity towards p53, but this interaction is disrupted by DNA damage.

Purpose of the Study:

  • To elucidate the mechanism by which DNA damage disrupts the Daxx-Mdm2 interaction.
  • To understand the role of Daxx phosphorylation in the DNA damage response pathway.
  • To investigate the functional consequences of Daxx-Mdm2 dissociation on p53 activation.

Main Methods:

  • Investigated Daxx phosphorylation in response to DNA damage using ATM-dependent assays.
  • Identified the specific ATM phosphorylation site on Daxx (Ser564).
  • Utilized biochemical and cellular assays to assess the impact of Daxx phosphorylation on Daxx-Mdm2 interaction and p53 activation.

Main Results:

  • DNA damage induces ATM-dependent phosphorylation of Daxx at Ser564.
  • Phosphorylation of Daxx at Ser564 occurs rapidly and precedes p53 activation.
  • Inhibition of Daxx phosphorylation prevents Daxx-Mdm2 dissociation, stabilizes Mdm2, and blocks p53 activation.

Conclusions:

  • ATM-mediated phosphorylation of Daxx at Ser564 is a critical event in the DNA damage response.
  • This phosphorylation disrupts the Daxx-Mdm2 interaction, facilitating the activation of the tumor suppressor p53.
  • The findings reveal a novel regulatory mechanism controlling p53 stability and function.

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