DNA-dependent protein kinase acts upstream of p53 in response to DNA damage

Nature. 1998 Aug 13;394(6694):700-4. doi: 10.1038/29343.

Abstract

The tumour suppressor p53 becomes activated as a transcription factor in response to DNA damage, but the mechanism for this activation is unclear. A good candidate for an upstream activator of p53 is the DNA-dependent protein kinase (DNA-PK) that depends on the presence of DNA breaks for its activity. Here we investigate the link between DNA damage and the activation of DNA-PK and of p53. To determine whether DNA-PK is an upstream mediator of the p53 DNA-damage response, we analysed a severe combined-immunodeficiency (SCID) mouse cell line, SCGR11, and the human glioma cell line M059J . Both cell lines lack any detectable DNA-PK activity. We find that p53 is incapable of binding to DNA in the absence of DNA-PK, that DNA-PK is necessary but not sufficient for activation of p53 sequence-specific DNA binding, and that this activation occurs in response to DNA damage. Our results establish DNA-PK as a link between DNA damage and p53 activation, and reveal the existence of a mammalian DNA-damage-response pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Cyclins / genetics
  • DNA / metabolism
  • DNA Damage*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Enzyme Activation
  • Enzyme Inhibitors
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Molecular Sequence Data
  • Nuclear Proteins
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • DNA
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein Serine-Threonine Kinases