A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination.
Journal:
Immunity 1998 SepAuthors:
Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver DT, Alt FW
Abstract
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 g
...[more]rowth 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.[less]
Mesh Headings:
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