Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice

Y Gu, JA Sekiguchi, Y Gao, P Dikkes… - Proceedings of the …, 2000 - National Acad Sciences
Y Gu, JA Sekiguchi, Y Gao, P Dikkes, K Frank, D Ferguson, P Hasty, J Chun, FW Alt
Proceedings of the National Academy of Sciences, 2000National Acad Sciences
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 …
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.
National Acad Sciences