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-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.
Kurimasa
A
A
Life Sciences Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Ouyang
H
H
Dong
L J
LJ
Wang
S
S
Li
X
X
Cordon-Cardo
C
C
Chen
D J
DJ
Li
G C
GC
D000818:Animals; D034961:Antigens, Nuclear; D020134:Catalytic Domain; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002588:Cesium Radioisotopes; D004265:DNA Helicases; D004254:DNA Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D005091:Exons; D005720:Gamma Rays; D005838:Genotype; D006965:Hyperplasia; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007413:Intestinal Mucosa / Q000473:pathology*; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D000072200:Ku Autoantigen; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013539:Simian virus 40 / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism; D045567:VDJ Recombinases