Topoisomerase IIα (Topo IIα), a well-conserved double-stranded DNA (dsDNA)-specific decatenase, processes dsDNA catenanes resulting from DNA replication during mitosis. Topo IIα defects lead to an accumulation of ultrafine anaphase bridges (UFBs), a type of chromosome non-disjunction. Topo IIα has been reported to resolve DNA anaphase threads, possibly accounting for the increase in UFB frequency upon Topo IIα inhibition. We hypothesized that the excess UFBs might also result, at least in part, from an impairment of the prevention of UFB formation by Topo IIα. We found that Topo IIα inhibition promotes UFB formation without affecting the global disappearance of UFBs during mitosis, but leads to an aberrant UFB resolution generating DNA damage within the next G1. Moreover, we demonstrated that Topo IIα inhibition promotes the formation of two types of UFBs depending on cell cycle phase. Topo IIα inhibition during S-phase compromises complete DNA replication, leading to the formation of UFB-containing unreplicated DNA, whereas Topo IIα inhibition during mitosis impedes DNA decatenation at metaphase-anaphase transition, leading to the formation of UFB-containing DNA catenanes. Thus, Topo IIα activity is essential to prevent UFB formation in a cell-cycle-dependent manner and to promote DNA damage-free resolution of UFBs.

中文翻译：

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拓扑异构酶IIα通过两种机制阻止超细后期桥键。

拓扑异构酶IIα（TopoIIα）是一种保存良好的双链DNA（dsDNA）特异性脱氢酶，可处理有丝分裂期间DNA复制产生的dsDNA链烯。TopoIIα缺陷导致超细后期桥（UFB）的积累，这是一种染色体非分离的类型。据报道，TopoIIα可以解析DNA后期线，这可能解释了TopoIIα抑制后UFB频率的增加。我们假设过量的UFB也可能至少部分是由于TopoIIα阻止了UFB形成的损害。我们发现，TopoIIα抑制作用促进了UFB的形成，而不影响有丝分裂期间UFB的整体消失，但导致异常的UFB分辨率在下一个G1内产生DNA损伤。此外，我们证明了TopoIIα抑制作用会根据细胞周期阶段促进两种类型的UFB的形成。S期期间的TopoIIα抑制会破坏完整的DNA复制，从而导致包含UFB的未复制DNA的形成，而有丝分裂期间的TopoIIα抑制则会阻止DNA在中期-后期过渡时的脱级，从而导致包含UFB的DNA链烯的形成。因此，TopoIIα活性对于以细胞周期依赖性方式阻止UFB形成并促进UFB的无DNA损伤拆分至关重要。导致形成含UFB的DNA链烯。因此，TopoIIα活性对于以细胞周期依赖性方式阻止UFB形成并促进UFB的无DNA损伤拆分至关重要。导致形成含UFB的DNA链烯。因此，TopoIIα活性对于以细胞周期依赖性方式阻止UFB形成并促进UFB的无DNA损伤拆分至关重要。