Kratz Anne-Sophie, Richter Kai T, Schlosser Yvonne T, Schmitt Miriam, Shumilov Anatoliy, Delecluse Henri-Jacques, Hoffmann Ingrid
a Cell Cycle Control and Carcinogenesis, F045, German Cancer Research Center , Heidelberg , Germany.
b Pathogenesis of Virus Associated Tumors, F100, German Cancer Research Center , Heidelberg , Germany.
Cell Cycle. 2016 Dec 16;15(24):3419-3431. doi: 10.1080/15384101.2016.1246093. Epub 2016 Oct 18.
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是一种在基因组DNA中解决拓扑学限制的必需酶。它在后期解开相互缠绕的染色体从而导致染色体分离，以此维持基因组稳定性。在此，我们描述了一种先前未被认识到的调节拓扑异构酶IIα活性的机制，该机制依赖于F-box蛋白Fbxo28。我们发现，Fbxo28是一种进化上保守的蛋白，是正常有丝分裂进程所必需的。干扰Fbxo28的功能会导致中期到后期进程的延迟，从而产生有丝分裂缺陷，如落后染色体、多极纺锤体和多核化。此外，我们发现Fbxo28在整个细胞周期中与拓扑异构酶IIα相互作用并共定位。Fbxo28的缺失导致拓扑异构酶IIα依赖性DNA解连环活性增加。有趣的是，阻断Fbxo28与拓扑异构酶IIα之间的相互作用也会导致多核细胞的产生。我们的研究结果表明，Fbxo28调节拓扑异构酶IIα的解连环活性，并在维持基因组稳定性中发挥重要作用。
