d'Adda di Fagagna F, Hande M P, Tong W M, Roth D, Lansdorp P M, Wang Z Q, Jackson S P
Wellcome/CRC Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, United Kingdom.
Curr Biol. 2001 Aug 7;11(15):1192-6. doi: 10.1016/s0960-9822(01)00328-1.
DNA repair by nonhomologous end-joining (NHEJ) relies on the Ku70:Ku80 heterodimer in species ranging from yeast to man. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, Ku also controls telomere functions. Here, we show that Ku70, Ku80, and DNA-PKcs, with which Ku interacts, associate in vivo with telomeric DNA in several human cell types, and we show that these associations are not significantly affected by DNA-damaging agents. We also demonstrate that inactivation of Ku80 or Ku70 in the mouse yields telomeric shortening in various primary cell types at different developmental stages. By contrast, telomere length is not altered in cells impaired in XRCC4 or DNA ligase IV, two other NHEJ components. We also observe higher genomic instability in Ku-deficient cells than in XRCC4-null cells. This suggests that chromosomal instability of Ku-deficient cells results from a combination of compromised telomere stability and defective NHEJ.
从酵母到人类，非同源末端连接（NHEJ）介导的DNA修复均依赖于Ku70:Ku80异源二聚体。在酿酒酵母和粟酒裂殖酵母中，Ku还控制端粒功能。在此，我们发现，在几种人类细胞类型中，Ku70、Ku80以及与Ku相互作用的DNA-PKcs在体内与端粒DNA相关联，并且我们发现这些关联不受DNA损伤剂的显著影响。我们还证明，在小鼠中使Ku80或Ku70失活会导致不同发育阶段的各种原代细胞类型中端粒缩短。相比之下，在XRCC4或DNA连接酶IV（另外两个NHEJ组分）受损的细胞中，端粒长度未发生改变。我们还观察到，Ku缺陷细胞中的基因组不稳定性高于XRCC4缺失细胞。这表明，Ku缺陷细胞的染色体不稳定性是端粒稳定性受损和NHEJ缺陷共同作用的结果。
