DNA-dependent protein kinase-independent activation of p53 in response to DNA damage

Sandeep Burma, Akihiro Kurimasa, Guofeng Xie, Yoichi Taya, Ryoko Araki, Masumi Abe, Harry A. Crissman, Honghai Ouyang, Gloria C. Li, David J. Chen

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Phosphorylation at serine 15 of the human p53 tumor suppressor protein is induced by DNA damage and correlates with accumulation of p53 and its activation as a transcription factor. The DNA-dependent protein kinase (DNA- PK) can phosphorylate serine 15 of human p53 and the homologous serine 18 of murine p53 in vitro. Contradictory reports exist about the requirement for DNA-PK in vivo for p53 activation and cell cycle arrest in response to ionizing radiation. While primary SCID (severe combined immunodeficiency) cells, that have defective DNA-PK, show normal p53 activation and cell cycle arrest, a transcriptionally inert form of p53 is induced in the SCID cell line SCGR11. In order to unambiguously define the role of the DNA-PK catalytic subunit (DNA-PKcs) in p53 activation, we examined p53 phosphorylation in mouse embryonic fibroblasts (MEFs) from DNA-PKcs-null mice. We found a similar pattern of serine 18 phosphorylation and accumulation of p53 in response to irradiation in both control and DNA-PKcs- null MEFs. The induced p53 was capable of sequence-specific DNA binding even in the absence of DNA-PKcs. Transactivation of the cyclin-dependent-kinase inhibitor p21, a downstream target of p53, and the G1 cell cycle checkpoint were also found to be normal in the DNA-PKcs -/- MEFs. Our results demonstrate that DNA-PKcs, unlike the related ATM protein, is not essential for the activation of p53 and G1 cell cycle arrest in response to ionizing radiation.

Original languageEnglish (US)
Pages (from-to)17139-17143
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number24
DOIs
StatePublished - Jun 11 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Burma, S., Kurimasa, A., Xie, G., Taya, Y., Araki, R., Abe, M., Crissman, H. A., Ouyang, H., Li, G. C., & Chen, D. J. (1999). DNA-dependent protein kinase-independent activation of p53 in response to DNA damage. Journal of Biological Chemistry, 274(24), 17139-17143. https://doi.org/10.1074/jbc.274.24.17139