Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver D T, Alt F W
Howard Hughes Medical Institute, The Children's Hospital, The Center for Blood Research and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Immunity. 1998 Sep;9(3):367-76. doi: 10.1016/s1074-7613(00)80619-6.
The DNA-dependent protein kinase (DNA-PK) consists of Ku70, Ku80, and a large catalytic subunit, DNA-PKcs. Targeted inactivation of the Ku70 or Ku80 genes results in elevated ionizing radiation (IR) sensitivity and inability to perform both V(D)J coding-end and signal (RS)-end joining in cells, with severe growth retardation plus immunodeficiency in mice. In contrast, we now demonstrate that DNA-PKcs-null mice generated by gene-targeted mutation, while also severely immunodeficient, exhibit no growth retardation. Furthermore, DNA-PKcs-null cells are blocked for V(D)J coding-end joining, but retain normal RS-end joining. Finally, while DNA-PK-null fibroblasts exhibited increased IR sensitivity, DNA-PKcs-deficient ES cells did not. We conclude that Ku70 and Ku80 may have functions in V(D)J recombination and DNA repair that are independent of DNA-PKcs.
DNA依赖性蛋白激酶（DNA-PK）由Ku70、Ku80和一个大型催化亚基DNA-PKcs组成。对Ku70或Ku80基因进行靶向失活会导致细胞对电离辐射（IR）的敏感性升高，并且无法进行V（D）J编码末端和信号（RS）末端连接，小鼠会出现严重的生长迟缓以及免疫缺陷。相比之下，我们现在证明，通过基因靶向突变产生的DNA-PKcs基因敲除小鼠虽然也存在严重的免疫缺陷，但并未表现出生长迟缓。此外，DNA-PKcs基因敲除细胞在V（D）J编码末端连接方面受阻，但保留了正常的RS末端连接。最后，虽然DNA-PK基因敲除的成纤维细胞对IR的敏感性增加，但DNA-PKcs缺陷的胚胎干细胞却没有。我们得出结论，Ku70和Ku80可能在V（D）J重组和DNA修复中具有独立于DNA-PKcs的功能。
