Abstract
Mammalian nonhomologous DNA end joining employs Ku70, Ku80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and DNA ligase IV (Lig4). Herein, we show that Ku70 and Ku80 deficiency but not DNA-PKcs deficiency results in dramatically increased death of developing embryonic neurons in mice. The Ku-deficient phenotype is qualitatively similar to, but less severe than, that associated with XRCC4 and Lig4 deficiency. The lack of a neuronal death phenotype in DNA-PKcs-deficient embryos and the milder phenotype of Ku-deficient versus XRCC4- or Lig4-deficient embryos correlate with relative leakiness of residual end joining in these mutant backgrounds as assayed by a V(D)J recombination end joining assay. We conclude that normal development of the nervous system depends on the four evolutionarily conserved nonhomologous DNA end joining factors.
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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Apoptosis
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Cells, Cultured
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Central Nervous System / abnormalities
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Central Nervous System / embryology*
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Central Nervous System / enzymology
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Cerebral Cortex / cytology
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Cerebral Cortex / pathology
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DNA Helicases*
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DNA Ligase ATP
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DNA Ligases / physiology
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DNA-Activated Protein Kinase
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DNA-Binding Proteins / physiology*
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Diencephalon / cytology
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Diencephalon / pathology
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Fibroblasts / metabolism
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In Situ Nick-End Labeling
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Ku Autoantigen
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Mice
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Mice, Mutant Strains
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Neurons / cytology
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Neurons / pathology
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Nuclear Proteins / physiology*
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Phenotype
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Protein Serine-Threonine Kinases / physiology*
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Recombination, Genetic
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Spinal Cord / cytology
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Spinal Cord / pathology
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Time Factors
Substances
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Antigens, Nuclear
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DNA-Binding Proteins
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LIG4 protein, human
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Nuclear Proteins
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XRCC4 protein, human
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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
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DNA Ligases
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DNA Ligase ATP