Requirement for Ku80 in growth and immunoglobulin V(D)J recombination.
The DNA-dependent protein kinase (DNA-PK) is a mammalian serine/threonine kinase that is implicated in the repair of DNA double-strand breaks, DNA replication, transcription, and V(D)J recombination. To determine the role of the DNA-binding subunit of DNA-PK in vivo, we targeted Ku80 in mice. In mutant mice, T and B lymphocyte development is arrested at early progenitor stages and there is a profound deficiency in V(D)J rearrangement. Although Ku80-/- mice are viable and reproduce, they are 40-60% of the size of littermate controls. Consistent with this growth defect, fibroblasts derived from Ku80-/- embryos showed an early loss of proliferating cells, a prolonged doubling time, and intact cell-cycle checkpoints that prevented cells with damaged DNA from entering the cell-cycle. The unexpected growth phenotype suggests a new and important link between Ku80 and growth control.
Nussenzweig
A
A
Department of Medical Physics, Memorial Sloan-Kettering Cancer Centre, New York 10021, USA.
Chen
C
C
da Costa Soares
V
V
Sanchez
M
M
Sokol
K
K
Nussenzweig
M C
MC
Li
G C
GC
D000818:Animals; D034961:Antigens, Nuclear; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D004265:DNA Helicases; D017931:DNA Primers; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D015321:Gene Rearrangement; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D018390:Gene Targeting; D006128:Growth / Q000502:physiology*; D000072200:Ku Autoantigen; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D034961:Antigens, Nuclear; D017931:DNA Primers; 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