DNA damage-induced apoptosis requires the DNA-dependent protein kinase, and is mediated by the latent population of p53

Richard A. Woo, Melissa T. Jack, Yang Xu, Sandeep Burma, David J. Chen, Patrick W.K. Lee

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Mouse embryo fibroblasts (MEFs) expressing the adenovirus E1A protein undergo apoptosis upon exposure to ionizing radiation. We show here that immediately following γ-irradiation, latent p53 formed a complex with the catalytic subunit of the DNA-dependent protein kinase (DNA-PKCS). The complex formation was DNase sensitive, suggesting that the proteins came together on the DNA, conceivably at strand breaks. This association was accompanied by phosphorylation of pre-existing, latent p53 at Ser18 (corresponding to Ser15 in human p53), which was not found in DNA-PKCS−/− cells. Most significantly, DNA damage-induced apoptosis was abolished in both DNA-PKCS−/− and p53−/− cells. In addition, blocking synthesis of inducible p53 by cycloheximide did not abrogate apoptosis, suggesting that the latent population of p53 is sufficient for executing the apoptotic program. Finally, E1A-expressing MEFs from a p53 'knock-in' mouse where Ser18 was mutated to an alanine had an attenuated apoptotic response, indicating that phosphorylation of this site by DNA-PK is a contributing factor for apoptosis.

Original languageEnglish (US)
Pages (from-to)3000-3008
Number of pages9
JournalEMBO Journal
Volume21
Issue number12
DOIs
StatePublished - Jun 17 2002

Keywords

  • Apoptosis
  • DNA damage
  • DNA-dependent protein kinase
  • P53
  • Ser15

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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