TOPOISOMERASE IIa PREVENTS ULTRAFINE ANAPHASE BRIDGES BY TWO MECHANISMS

Topoisomerase IIa (Topo IIa), a well-conserved double-stranded DNA (dsDNA)-specific decatenase, processes dsDNA catenanes resulting from DNA replication during mitosis. Topo IIa defects lead to an accumulation of ultrafine anaphase bridges (UFBs), a type of chromosome non-disjunction. Topo IIa has been reported to resolve DNA anaphase threads, possibly accounting for the increase in UFB frequency upon Topo IIa 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 IIa. We found that Topo IIa 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 IIa inhibition promotes the formation of two types of UFBs depending on cell-cycle phase. Topo IIa inhibition during S-phase compromises complete DNA replication, leading to the formation of UFB-containing unreplicated DNA, whereas Topo IIa inhibition during mitosis impedes DNA decatenation at metaphase-anaphase transition, leading to the formation of UFB-containing DNA catenanes. Thus, Topo IIa activity is essential to prevent UFB formation in a cell-cycle dependent manner and to promote DNA-damage free resolution of UFBs.