Catalytic subunit of DNA-dependent protein kinase: Impact on lymphocyte development and tumorigenesis
- 16 February 1999
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 96 (4) , 1403-1408
- https://doi.org/10.1073/pnas.96.4.1403
Abstract
The DNA-dependent protein kinase (DNA-PK) consists of a heterodimer DNA-binding complex, Ku70 and Ku80, and a large catalytic subunit, DNA-PKcs. To examine the role of DNA-PKcs in lymphocyte development, radiation sensitivity, and tumorigenesis, we disrupted the mouse DNA-PKcs by homologous recombination. DNA-PKcs-null mice exhibit neither growth retardation nor a high frequency of T cell lymphoma development, but show severe immunodeficiency and radiation hypersensitivity. In contrast to the Ku70-/- and Ku80-/- phenotype, DNA-PKcs-null mice are blocked for V(D)J coding but not for signal-end joint formation. Furthermore, inactivation of DNA-PKcs leads to hyperplasia and dysplasia of the intestinal mucosa and production of aberrant crypt foci, suggesting a novel role of DNA-PKcs in tumor suppression.Keywords
This publication has 33 references indexed in Scilit:
- DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locusNature Genetics, 1997
- Ku70 Is Required for DNA Repair but Not for T Cell Antigen Receptor Gene Recombination In VivoThe Journal of Experimental Medicine, 1997
- Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy studiesThe EMBO Journal, 1997
- Characterization of Two DNA Double-stranded Break Repair-deficient Cell Lines That Express Inactive DNA-dependent Protein Kinase Catalytic SubunitsPublished by Elsevier ,1997
- Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse.Proceedings of the National Academy of Sciences, 1996
- Requirement for Ku80 in growth and immunoglobulin V(D)J recombinationNature, 1996
- Role of aberrant crypt foci in understanding the pathogenesis of colon cancerCancer Letters, 1995
- Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutationCell, 1995
- Stimulation of the DNA-dependent Protein Kinase by RNA Polymerase II Transcriptional Activator ProteinsJournal of Biological Chemistry, 1995
- The multistep nature of cancerTrends in Genetics, 1993