Hartley K O, Gell D, Smith G C, Zhang H, Divecha N, Connelly M A, Admon A, Lees-Miller S P, Anderson C W, Jackson S P
Wellcome Trust/Cancer Research Campaign Institute, Cambridge University, England.
Cell. 1995 Sep 8;82(5):849-56. doi: 10.1016/0092-8674(95)90482-4.
DNA-dependent protein kinase (DNA-PK), which is involved in DNA double-stranded break repair and V(D)J recombination, comprises a DNA-targeting component called Ku and an approximately 460 kDa catalytic subunit, DNA-PKcs. Here, we describe the cloning of the DNA-PKcs cDNA and show that DNA-PKcs falls into the phosphatidylinositol (PI) 3-kinase family. Biochemical assays, however, indicate that DNA-PK phosphorylates proteins but has no detectable activity toward lipids. Strikingly, DNA-PKcs is most similar to PI kinase family members involved in cell cycle control, DNA repair, and DNA damage responses. These include the FKBP12-rapamycin-binding proteins Tor1p, Tor2p, and FRAP, S. pombe rad3, and the product of the ataxia telangiectasia gene, mutations in which lead to genomic instability and predisposition to cancer. The relationship of these proteins to DNA-PKcs provides important clues to their mechanisms of action.
DNA依赖性蛋白激酶(DNA-PK)参与DNA双链断裂修复和V(D)J重组,它由一个名为Ku的DNA靶向成分和一个约460 kDa的催化亚基DNA-PKcs组成。在此,我们描述了DNA-PKcs cDNA的克隆,并表明DNA-PKcs属于磷脂酰肌醇(PI)3激酶家族。然而,生化分析表明,DNA-PK使蛋白质磷酸化,但对脂质没有可检测到的活性。引人注目的是,DNA-PKcs与参与细胞周期控制、DNA修复和DNA损伤反应的PI激酶家族成员最为相似。这些成员包括FKBP12-雷帕霉素结合蛋白Tor1p、Tor2p和FRAP、粟酒裂殖酵母rad3以及共济失调毛细血管扩张症基因的产物,该基因的突变会导致基因组不稳定和易患癌症。这些蛋白质与DNA-PKcs的关系为它们的作用机制提供了重要线索。