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DNA-PK suppresses a p53-independent apoptotic response to DNA damage

Kay E Gurley1, Russell Moser, Yansong Gu

  • 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

EMBO Reports
|December 6, 2008
PubMed

Insights

The tumor suppressor p53 triggers apoptosis after DNA damage. Inactivating DNA-dependent protein kinase (DNA-PK) in p53-deficient cells restores apoptosis, revealing a p53-independent DNA damage response pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The tumor suppressor protein p53 is crucial for initiating apoptosis in response to DNA damage.
  • Defects in p53 function lead to resistance to apoptosis, contributing to tumor development.

Purpose of the Study:

  • To investigate the role of DNA-dependent protein kinase (DNA-PK) in p53-mediated apoptosis.
  • To identify alternative apoptotic pathways in the absence of functional p53.

Main Methods:

  • Utilized genetically engineered mouse models (double-null mice) lacking p53 and specific DNA repair proteins (DNA-PKcs, Ku80, Ku70, Lig4, Atm).
  • Assessed radiation-induced apoptosis in intestinal crypt cells.
  • Monitored key apoptotic markers including phospho-CHK2, cleaved caspase-3, and cleaved caspase-9.

Main Results:

  • p53-deficient cells exhibited resistance to radiation-induced apoptosis.
  • Inactivation of DNA-PK (DNA-PKcs, Ku80, or Ku70) in p53-deficient cells fully restored apoptosis.
  • This p53-independent apoptosis was specific to DNA-PK loss and not observed in Lig4/p53 or Atm/p53 double-null mice.
  • The restored apoptosis involved increased phospho-CHK2 and cleaved caspases 3 and 9.

Conclusions:

  • Two distinct and equally effective apoptotic pathways exist in response to DNA damage.
  • One pathway is dependent on p53.
  • The other pathway is independent of p53 and is engaged upon the inactivation of DNA-PK.

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