Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
1] Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK [2] Institute of Biochemistry and Biophysics, PAS, 02-106 Warsaw, Poland.
Nat Commun. 2015 Mar 12;6:6572. doi: 10.1038/ncomms7572.
During mitosis, sister chromatids must be faithfully segregated to ensure that daughter cells receive one copy of each chromosome. However, following replication they often remain entangled. Topoisomerase IIα (TOP2A) has been proposed to resolve such entanglements, but the mechanisms governing TOP2A recruitment to these structures remain poorly understood. Here, we identify TOPBP1 as a novel interactor of TOP2A, and reveal that it is required for TOP2A recruitment to ultra-fine anaphase bridges (UFBs) in mitosis. The C-terminal region of TOPBP1 interacts with TOP2A, and TOPBP1 recruitment to UFBs requires its BRCT domain 5. Depletion of TOPBP1 leads to accumulation of UFBs, the majority of which arise from centromeric loci. Accordingly, expression of a TOPBP1 mutant that is defective in TOP2A binding phenocopies TOP2A depletion. These findings provide new mechanistic insights into how TOP2A promotes resolution of UFBs during mitosis, and highlights a pivotal role for TOPBP1 in this process.
在有丝分裂过程中，姐妹染色单体必须准确分离，以确保子细胞获得每条染色体的一份拷贝。然而，在复制后，它们经常仍然纠缠在一起。拓扑异构酶 IIα（TOP2A）被提议用于解决这些缠绕，但调控 TOP2A 向这些结构募集的机制仍知之甚少。在这里，我们鉴定出 TOPBP1 是 TOP2A 的一种新型相互作用蛋白，并揭示它是 TOP2A 向有丝分裂中超微后期桥（UFBs）募集所必需的。TOPBP1 的 C 末端区域与 TOP2A 相互作用，TOPBP1 向 UFBs 的募集需要其 BRCT 结构域 5。TOPBP1 的耗竭导致 UFBs 的积累，其中大多数源自着丝粒位点。相应地，表达一种在 TOP2A 结合中存在缺陷的 TOPBP1 突变体可模拟 TOP2A 耗竭的表型。这些发现为 TOP2A 在有丝分裂中促进 UFBs 解析的机制提供了新的见解，并强调了 TOPBP1 在这个过程中的关键作用。
