DNA-dependent protein kinase and related proteins

Biochem Soc Symp. 1999;64:91-104.

Abstract

The DNA-dependent protein kinase (DNA-PK) is a nuclear protein serine/threonine kinase that must bind to DNA double-strand breaks to be active. We and others have shown that it is a multiprotein complex comprising an approx. 465 kDa catalytic subunit (DNA-PKcs) and a DNA-binding component, Ku. Notably, cells defective in DNA-PK are hypersensitive to ionizing radiation. Thus X-ray-sensitive hamster xrs-6 cells are mutated in Ku, and rodent V3 cells and cells of the severe combined immune-deficient (Scid) mouse lack a functional DNA-PKcs. Cloning of the DNA-PKcs cDNA revealed that it falls into the phosphatidylinositol (PI) 3-kinase family of proteins. However, biochemical assays indicate that DNA-PK contains no intrinsic lipid kinase activity, but is instead a serine/threonine kinase. We have also found that DNA-PK activity can be inhibited by the PI 3-kinase inhibitors wortmannin and LY294002. Consistent with its proposed role in genome surveillance and the detection of DNA damage, DNA-PKcs is most similar to a subset of proteins involved in cell-cycle checkpoint control and signalling of DNA damage. Furthermore, the recent cloning of the gene mutated in ataxia-telangiectasia (A-T) patients, named ATM (A-T mutated), has revealed that the product of this gene is also a PI 3-kinase family member and is related to DNA-PKcs. Although much is known about the clinical symptoms and cellular phenotypes that arise from disruption of the A-T gene, little is known about the biochemical action of ATM in response to DNA damage. Given its sequence similarity with DNA-PKcs, we speculate that ATM may function in a manner similar to DNA-PK.

Publication types

  • Review

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Chromones / pharmacology
  • DNA / metabolism*
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / pharmacology
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Conformation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Substrate Specificity
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • DNA
  • DNA-Activated Protein Kinase
  • Protein-Serine-Threonine Kinases
  • Wortmannin