Nussenzweig A, Chen C, da Costa Soares V, Sanchez M, Sokol K, Nussenzweig M C, Li G C
Department of Medical Physics, Memorial Sloan-Kettering Cancer Centre, New York 10021, USA.
Nature. 1996 Aug 8;382(6591):551-5. doi: 10.1038/382551a0.
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.
DNA依赖性蛋白激酶（DNA-PK）是一种哺乳动物丝氨酸/苏氨酸激酶，参与DNA双链断裂修复、DNA复制、转录及V（D）J重组。为确定DNA-PK的DNA结合亚基在体内的作用，我们对小鼠中的Ku80进行了靶向操作。在突变小鼠中，T和B淋巴细胞发育在早期祖细胞阶段停滞，V（D）J重排存在严重缺陷。尽管Ku80基因敲除小鼠能够存活并繁殖，但它们的体型只有同窝对照小鼠的40%-60%。与这种生长缺陷一致，源自Ku80基因敲除胚胎的成纤维细胞显示增殖细胞早期减少、倍增时间延长，且细胞周期检查点完整，可防止DNA受损的细胞进入细胞周期。这种意外的生长表型表明Ku80与生长控制之间存在新的重要联系。
