Fbxo28 promotes mitotic progression and regulates topoisomerase IIα-dependent DNA decatenation

Topoisomerase II alpha is an essential enzyme that resolves topological constraints in genomic DNA. It functions in disentangling intertwined chromosomes during anaphase leading to chromosome segregation thus preserving genomic stability. Here we describe a previously unrecognized mechanism regulating topoisomerase II alpha activity that is dependent on the F-box protein Fbxo28. We find that Fbxo28, an evolutionarily conserved protein, is required for proper mitotic progression. Interfering with Fbxo28 function leads to a delay in metaphase-to-anaphase progression resulting in mitotic defects as lagging chromosomes, multipolar spindles and multinucleation. Furthermore, we find that Fbxo28 interacts and colocalizes with topoisomerase II alpha throughout the cell cycle. Depletion of Fbxo28 results in an increase in topoisomerase II alpha-dependent DNA decatenation activity. Interestingly, blocking the interaction between Fbxo28 and topoisomerase II alpha also results in multinucleated cells. Our findings suggest that Fbxo28 regulates topoisomerase II alpha decatenation activity and plays an important role in maintaining genomic stability.