Catalytic subunit of DNA-dependent protein kinase: Impact on lymphocyte development and tumorigenesis

The DNA-dependent protein kinase (DNA-PK) consists of a heterodimer DNA-bin ding complex, Ku70 and Ku80, and a large catalytic subunit, DNA-PKcs, To ex amine the role of DNA-PKcs in lymphocyte development, radiation sensitivity , and tumorigenesis, we disrupted the mouse DNA-PKcs by homologous recombin ation. DNA-PKcs-null mice exhibit neither growth retardation nor a high fre quency of T cell lymphoma development, but show severe immunodeficiency and radiation hypersensitivity. In contrast to the Ku70-/- and Ku80-/- phenoty pe, 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 fo ci, suggesting a novel role of DNA-PKcs in tumor suppression.