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Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress

C Bassi1, J Ho, T Srikumar

  • 1Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

Science (New York, N.Y.)
|July 27, 2013
PubMed

Insights

SUMOylation controls nuclear PTEN localization, which is crucial for DNA damage response. Loss of nuclear PTEN increases sensitivity to genotoxic stress, impacting cancer therapy strategies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is frequently lost in human cancers.
  • PTEN's cytoplasmic role in antagonizing the phosphatidylinositol 3-kinase (PI3K) pathway is established, but its nuclear function is unclear.

Purpose of the Study:

  • To investigate the role of PTEN's nuclear localization in cellular response to DNA damage.
  • To elucidate the regulatory mechanisms controlling PTEN's nuclear import and export.

Main Methods:

  • SUMOylation assays to assess PTEN modification.
  • Cellular fractionation and microscopy to determine PTEN localization.
  • DNA damage sensitivity assays in response to genotoxic stress.
  • In vitro and in vivo experiments using PTEN-deficient models.

Main Results:

  • SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN regulates its nuclear localization.
  • Genotoxic stress induces rapid nuclear exclusion of SUMO-PTEN, dependent on ataxia telangiectasia mutated (ATM) kinase.
  • Cells lacking nuclear PTEN exhibit hypersensitivity to DNA damage.
  • PTEN-deficient cells are susceptible to killing by combined genotoxic stress and PI3K inhibition.

Conclusions:

  • PTEN's nuclear localization, controlled by SUMOylation and ATM, is critical for DNA damage response.
  • Targeting nuclear PTEN dynamics or combining PI3K inhibition with genotoxic stress may offer novel therapeutic strategies for PTEN-deficient cancers.

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