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ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage

Naoe Taira1, Hiroyuki Yamamoto, Tomoko Yamaguchi

  • 1Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.

The Journal of Biological Chemistry
|December 8, 2009
PubMed

Insights

DNA damage triggers the tumor suppressor p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The tumor suppressor p53 is crucial for cellular responses to DNA damage, including apoptosis.
  • Phosphorylation of p53 at Ser-46 is a key step for initiating programmed cell death.
  • DYRK2 kinase phosphorylates p53 at Ser-46, promoting apoptosis, but its intracellular regulation is unclear.

Purpose of the Study:

  • To elucidate the mechanisms controlling the stability and nuclear localization of DYRK2.
  • To understand how DYRK2's pro-apoptotic function is regulated in response to genotoxic stress.

Main Methods:

  • Immunoprecipitation and Western blotting to detect protein interactions and stability.
  • Cellular localization studies using microscopy.
  • Treatment with genotoxic agents and proteasome inhibitors.

Main Results:

  • DYRK2 possesses a functional nuclear localization signal.
  • MDM2 ubiquitinates nuclear DYRK2, leading to its degradation under normal conditions.
  • ATM-mediated phosphorylation of DYRK2 at Thr-33 and Ser-369 upon genotoxic stress causes dissociation from MDM2, stabilizing DYRK2 and promoting p53 phosphorylation at Ser-46.

Conclusions:

  • ATM-dependent phosphorylation regulates DYRK2 stability and its pro-apoptotic activity.
  • This pathway highlights a novel mechanism for controlling p53-mediated apoptosis in response to DNA damage.

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