Growth retardation and leaky SCID phenotype of Ku70-deficient mice.
Ku70, Ku80, and DNA-PKcs are subunits of the DNA-dependent protein kinase (DNA-PK), an enzyme implicated in DNA double-stranded break repair and V(D)J recombination. Our Ku70-deficient mice were about 50% the size of control littermates, and their fibroblasts were ionizing radiation sensitive and displayed premature senescence associated with the accumulation of nondividing cells. Ku70-deficient mice lacked mature B cells or serum immunoglobulin but, unexpectedly, reproducibly developed small populations of thymic and peripheral alpha/beta T lineage cells and had a significant incidence of thymic lymphomas. In association with B and T cell developmental defects, Ku70-deficient cells were severely impaired for joining of V(D)J coding and recombination signal sequences. These unanticipated features of the Ku70-deficient phenotype with respect to lymphocyte development and V(D)J recombination may reflect differential functions of the three DNA-PK components.
Gu
Y
Y
The Howard Hughes Medical Institute, Children's Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Seidl
K J
KJ
Rathbun
G A
GA
Zhu
C
C
Manis
J P
JP
van der Stoep
N
N
Davidson
L
L
Cheng
H L
HL
Sekiguchi
J M
JM
Frank
K
K
Stanhope-Baker
P
P
Schlissel
M S
MS
Roth
D B
DB
Alt
F W
FW
D000818:Animals; D034961:Antigens, Nuclear; D001402:B-Lymphocytes / Q000166:cytology; D002453:Cell Cycle; D002478:Cells, Cultured; D016922:Cellular Senescence; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000502:physiology*; D005317:Fetal Growth Retardation / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID / Q000235:genetics*; D009687:Nuclear Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D013601:T-Lymphocytes / Q000166:cytology; D013953:Thymus Neoplasms / Q000235:genetics
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen