Luo Kuntian, Yuan Jian, Chen Junjie, Lou Zhenkun
Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Nat Cell Biol. 2009 Feb;11(2):204-10. doi: 10.1038/ncb1828. Epub 2008 Dec 21.
Topoisomerase II (Topo II) is required to separate intertwined sister chromatids before chromosome segregation can occur in mitosis. However, it remains to be resolved whether Topo II has any role in checkpoint control. Here we report that when phosphorylated, Ser 1524 of Topo IIalpha acts as a binding site for the BRCT domain of MDC1 (mediator of DNA damage checkpoint protein-1), thereby recruiting MDC1 to chromatin. Although Topo IIalpha-MDC1 interaction is not required for checkpoint activation induced by DNA damage, it is required for activation of the decatenation checkpoint. Mutation of Ser 1524 results in a defective decatenation checkpoint. These results reveal an important role of Topo II in checkpoint activation and in the maintenance of genomic stability.
在有丝分裂中，染色体分离发生之前，拓扑异构酶II（Topo II）是解开相互缠绕的姐妹染色单体所必需的。然而，Topo II在检查点控制中是否发挥作用仍有待解决。在此我们报告，当Topo IIα的丝氨酸1524被磷酸化时，它作为MDC1（DNA损伤检查点蛋白-1的介质）的BRCT结构域的结合位点，从而将MDC1招募到染色质上。虽然DNA损伤诱导的检查点激活不需要Topo IIα-MDC1相互作用，但它是解连环检查点激活所必需的。丝氨酸1524的突变导致解连环检查点缺陷。这些结果揭示了Topo II在检查点激活和维持基因组稳定性中的重要作用。
