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A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination.

The DNA-dependent protein kinase (DNA-PK) consists of Ku70, Ku80, and a large catalytic subunit, DNA-PKcs. Targeted inactivation of the Ku70 or Ku80 genes results in elevated ionizing radiation (IR) sensitivity and inability to perform both V(D)J coding-end and signal (RS)-end joining in cells, with severe growth retardation plus immunodeficiency in mice. In contrast, we now demonstrate that DNA-PKcs-null mice generated by gene-targeted mutation, while also severely immunodeficient, exhibit no growth retardation. Furthermore, DNA-PKcs-null cells are blocked for V(D)J coding-end joining, but retain normal RS-end joining. Finally, while DNA-PK-null fibroblasts exhibited increased IR sensitivity, DNA-PKcs-deficient ES cells did not. We conclude that Ku70 and Ku80 may have functions in V(D)J recombination and DNA repair that are independent of DNA-PKcs.

Pubmed ID: 9768756

Authors

  • Gao Y
  • Chaudhuri J
  • Zhu C
  • Davidson L
  • Weaver DT
  • Alt FW

Journal

Immunity

Publication Data

September 28, 1998

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI20047
  • Agency: NIAID NIH HHS, Id: AI35714

Mesh Terms

  • Animals
  • Antigens, Nuclear
  • DNA Helicases
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins
  • Embryo, Mammalian
  • Female
  • Fibroblasts
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • Gene Targeting
  • Immunoglobulin Joining Region
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Nuclear Proteins
  • Phenotype
  • Protein-Serine-Threonine Kinases
  • Radiation, Ionizing
  • Severe Combined Immunodeficiency
  • Signal Transduction
  • Stem Cells
  • Thymus Gland