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

Kay E. Gurley, Russell Moser, Yansong Gu, Paul Hasty, Christopher J. Kemp

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

p53 is required for DNA damage-induced apoptosis, which is central to its function as a tumour suppressor. Here, we show that the apoptotic defect of p53-deficient cells is nearly completely rescued by inactivation of any of the three subunits of the DNA repair holoenzyme DNA-dependent protein kinase (DNA-PK). Intestinal crypt cells from p53 nullizygous mice were resistant to radiation-induced apoptosis, whereas apoptosis in DNA-PKcs/p53, Ku80/p53 and Ku70/p53 double-null mice was quantitatively equivalent to that seen in wild-type mice. This p53-independent apoptotic response was specific to the loss of DNA-PK, as it was not seen in ligase IV (Lig4)/p53 or ataxia telangiectasia mutated (Atm)/p53 double-null mice. Furthermore, it was associated with an increase in phospho-checkpoint kinase 2 (CHK2), and cleaved caspases 3 and 9, the latter indicating engagement of the intrinsic apoptotic pathway. This shows that there are two separate, but equally effective, apoptotic responses to DNA damage: one is p53 dependent and the other, engaged in the absence of DNA-PK, does not require p53.

Original languageEnglish (US)
Pages (from-to)87-93
Number of pages7
JournalEMBO Reports
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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