Topoisomerase IIα Prevents, But Does Not Resolve, Ultrafine Anaphase Bridges By Two Mechanisms

Topoisomerase II (Topo II), a well-conserved double-stranded DNA (dsDNA)-specific decatenase, processes dsDNA catenanes resulting from DNA replication during mitosis. Topo II defects lead to an accumulation of ultrafine anaphase bridges (UFBs), a type of chromosome non-disjunction. Topo II has been reported to resolve DNA anaphase threads, possibly accounting for the increase in UFB frequency upon Topo II 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 II. We found that Topo II inhibition promotes UFB formation without affecting UFB resolution during anaphase. Moreover, we showed that Topo II inhibition promotes the formation of two types of UFBs depending on cell-cycle phase. Topo II inhibition during S-phase compromises complete DNA replication, leading to the formation of UFB-containing unreplicated DNA, whereas Topo II inhibition during mitosis impedes DNA decatenation at metaphase-anaphase transition, leading to the formation of UFB-containing DNA catenanes. Thus, Topo II activity is essential to prevent UFB formation in a cell-cycle dependent manner, but dispensable for UFB resolution during anaphase.