title: TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution.
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.
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Ronan
authors.initials: R
authors.lastname: Broderick
authors.affiliation: 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.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Nieminuszczy
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Andrew N
authors.identifier: 000000031979021X
authors.initials: AN
authors.lastname: Blackford
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Alicja
authors.initials: A
authors.lastname: Winczura
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Niedzwiedz
mesh_terms: D000705:Anaphase; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002503:Centromere / Q000648:ultrastructure; D002842:Chromatids / Q000737:chemistry; D002875:Chromosomes / Q000648:ultrastructure; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C110513:TOPBP1 protein, human; D049452:Green Fluorescent Proteins; D004247:DNA; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human