TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution
Copyright policy )TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution
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.
- University of Copenhagen Denmark
- Polish Academy of Sciences Poland
- Institute of Cancer Research United Kingdom
- MRC Weatherall Institute of Molecular Medicine United Kingdom
- University of Cambridge United Kingdom
Carrier Proteins/metabolism, Cell Cycle Proteins, Chromatids/chemistry, Poly-ADP-Ribose Binding Proteins, Microscopy, Tumor, DNA-Binding Proteins/metabolism, Nuclear Proteins, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Neoplasm/metabolism, Protein Binding, Protein Structure, Centromere, Green Fluorescent Proteins, Mitosis, Centromere/ultrastructure, Chromatids, Type II, Fluorescence, Article, Chromosomes, Cell Line, Antigens, Neoplasm, Cell Line, Tumor, Humans, Antigens, DNA/chemistry, Green Fluorescent Proteins/metabolism, Nuclear Proteins/metabolism, Neoplastic, Cell Cycle Proteins/metabolism, 500, Type II/metabolism, DNA, Chromosomes/ultrastructure, Protein Structure, Tertiary, DNA Topoisomerases, Type II, HEK293 Cells, Gene Expression Regulation, Microscopy, Fluorescence, Hela Cells, Mutation, Neoplasm, Anaphase, Carrier Proteins, DNA Topoisomerases, Tertiary, HeLa Cells
Carrier Proteins/metabolism, Cell Cycle Proteins, Chromatids/chemistry, Poly-ADP-Ribose Binding Proteins, Microscopy, Tumor, DNA-Binding Proteins/metabolism, Nuclear Proteins, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Neoplasm/metabolism, Protein Binding, Protein Structure, Centromere, Green Fluorescent Proteins, Mitosis, Centromere/ultrastructure, Chromatids, Type II, Fluorescence, Article, Chromosomes, Cell Line, Antigens, Neoplasm, Cell Line, Tumor, Humans, Antigens, DNA/chemistry, Green Fluorescent Proteins/metabolism, Nuclear Proteins/metabolism, Neoplastic, Cell Cycle Proteins/metabolism, 500, Type II/metabolism, DNA, Chromosomes/ultrastructure, Protein Structure, Tertiary, DNA Topoisomerases, Type II, HEK293 Cells, Gene Expression Regulation, Microscopy, Fluorescence, Hela Cells, Mutation, Neoplasm, Anaphase, Carrier Proteins, DNA Topoisomerases, Tertiary, HeLa Cells
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