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

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

^§Department of Radiation Oncology, ^‡Department of Medical Physics, and ^¶Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY 10021; and ^*Life Sciences Division, Los Alamos National Laboratory, Los Alamos, NM 87545

Communicated by James C. Wang, Harvard University, Cambridge, MA (received for review October 21, 1998)

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.

Footnotes

↵ † These authors contributed equally to this work.
↵ ‖ To whom reprint requests should be addressed. e-mail: dchen{at}lanl.gov.
↵ ** To whom reprint requests should be addressed at: Memorial Sloan–Kettering Cancer Center, Box 72, 1275 York Avenue, New York, NY 10021. e-mail: g-li{at}ski.mskcc.org.
ABBREVIATIONS:

DNA-PK,

DNA-dependent protein kinase;

SCID,

severe combined immunodeficiency;

V(D)J,

variable (diversity) joining;

DNA-PKcs,

catalytic subunit of DNA-dependent protein kinase;

ES,

embryonic stem;

RT-PCR,

reverse transcription–PCR;

TCR,

T cell antigen receptor;

BM,

bone marrow