Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Nuclear*
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Base Sequence
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Cell Cycle / physiology
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Cell Division / physiology
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Cell Line
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DNA Helicases*
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DNA Primers
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DNA-Activated Protein Kinase
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Fibroblasts / cytology
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Gene Rearrangement*
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Gene Rearrangement, B-Lymphocyte
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Gene Rearrangement, T-Lymphocyte
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Gene Targeting
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Growth / physiology*
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Ku Autoantigen
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Lymphocytes / cytology
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Mice
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Mice, SCID
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
Substances
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Antigens, Nuclear
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DNA Primers
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DNA-Binding Proteins
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Nuclear Proteins
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DNA-Activated Protein Kinase
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Protein Serine-Threonine Kinases
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DNA Helicases
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XRCC5 protein, human
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Xrcc6 protein, human
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Xrcc6 protein, mouse
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Ku Autoantigen