Topoisomerase IIα controls the decatenation checkpoint

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Abstract
Separation of intertwined sister chromatids, mediated by topoisomerase II, is essential for mitosis. In a separate mechanism, phosphorylation of topoisomerase II at Ser 1524 during the G2/M phase of the cell cycle recruits MDC1 to activate the decatenation checkpoint required for genomic stability. Topoisomerase II (Topo II) is required to separate intertwined sister chromatids before chromosome segregation can occur in mitosis1. 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 IIα 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 IIα–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.