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

Topoisomerase IIα 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 IIα 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 IIα throughout the cell cycle. Depletion of Fbxo28 results in an increase in topoisomerase IIα−dependent DNA decatenation activity. Interestingly, blocking the interaction between Fbxo28 and topoisomerase IIα also results in multinucleated cells. Our findings suggest that Fbxo28 regulates topoisomerase IIα decatenation activity and plays an important role in maintaining genomic stability.

拓扑异构酶IIα（Topoisomerase IIα）是一类可解决基因组DNA拓扑约束的必需酶。其在有丝分裂后期发挥作用，解开缠绕的染色体，介导染色体分离，进而维持基因组稳定性。本研究报道了一种此前未被发现的、依赖于F-box蛋白Fbxo28的拓扑异构酶IIα活性调控新机制。
我们发现，Fbxo28作为一种进化保守蛋白，是细胞正常有丝分裂进程所必需的。干扰Fbxo28的功能会导致细胞中期向后期的进程延迟，进而引发有丝分裂缺陷，具体表现为滞后染色体、多极纺锤体及多核化。
此外，我们还证实Fbxo28可在整个细胞周期中与拓扑异构酶IIα相互作用并共定位。敲低Fbxo28会使拓扑异构酶IIα依赖的DNA解连环活性显著升高。值得注意的是，阻断Fbxo28与拓扑异构酶IIα的相互作用同样会诱导多核细胞的产生。
本研究结果表明，Fbxo28可通过调控拓扑异构酶IIα的解连环活性，在维持基因组稳定性过程中发挥重要作用。