Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity.
The DNA-dependent protein kinase is a mammalian protein complex composed of Ku70, Ku80, and DNA-PKcs subunits that has been implicated in DNA double-strand break repair and V(D)J recombination. Here, by gene targeting, we have constructed a mouse with a disruption in the kinase domain of DNA-PKcs, generating an animal model completely devoid of DNA-PK activity. Our results demonstrate that DNA-PK activity is required for coding but not for signal join formation in mice. Although our DNA-PKcs defective mice closely resemble Scid mice, they differ by having elevated numbers of CD4+CD8+ thymocytes. This suggests that the Scid mice may not represent a null phenotype and may retain some residual DNA-PKcs function.
Taccioli
G E
GE
Department of Microbiology, Boston University School of Medicine, Massachusetts 02118, USA. taccioli@bu.edu
Amatucci
A G
AG
Beamish
H J
HJ
Gell
D
D
Xiang
X H
XH
Torres Arzayus
M I
MI
Priestley
A
A
Jackson
S P
SP
Marshak Rothstein
A
A
Jeggo
P A
PA
Herrera
V L
VL
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D002384:Catalysis; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000528:radiation effects; D018390:Gene Targeting; D019672:Genes, T-Cell Receptor / Q000235:genetics; D007136:Immunoglobulins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D017434:Protein Structure, Tertiary; D011836:Radiation Tolerance / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology
D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases