Abstract
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.
Highlights
During mitosis, sister chromatids must be faithfully segregated to ensure that daughter cells receive one copy of each chromosome
On the basis of these findings, we propose that Topoisomerase IIb-binding protein 1 (TOPBP1) recruits TOP2A to ultra-fine anaphase bridges (UFBs) to aid resolution of DNA entanglements between sister chromatids, and this function could contribute to the role that these proteins play in the maintenance of genome stability
Endogenous TOPBP1 was detected in reciprocal GFP–TOP2A immunoprecipitates from cell extracts (Fig. 1c), confirming that the two proteins likely exist in the same complex in cells
Summary
Sister chromatids must be faithfully segregated to ensure that daughter cells receive one copy of each chromosome. A subset of UFBs arise from common genomic fragile sites, which can be induced by replication stress, for example, treatment with aphidicolin[6] They most likely result from sister chromatid interlinks generated by unresolved replication intermediates, and are characterized by the presence of the Fanconi Anaemia (FA) protein FANCD2 forming foci localizing at either end of the bridge[6]. The majority of UFBs do not associate with the FA proteins, and the mechanism governing their resolution remains more enigmatic[9] These UFBs originate mainly from centromeric loci in the genome, which suggests that they arise from unresolved DNA catenanes of fully replicated DNA strands present in anaphase[3,9]. The mechanism of TOP2A recruitment to these structures or any role in their resolution is unclear and remains a key question in the field[9]
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