title: Fbxo28 promotes mitotic progression and regulates topoisomerase IIα-dependent DNA decatenation.
abstract: 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.
authors.affiliation: a Cell Cycle Control and Carcinogenesis, F045, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Kratz
authors.affiliation: a Cell Cycle Control and Carcinogenesis, F045, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Kai T
authors.initials: KT
authors.lastname: Richter
authors.affiliation: a Cell Cycle Control and Carcinogenesis, F045, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Yvonne T
authors.initials: YT
authors.lastname: Schlosser
authors.affiliation: a Cell Cycle Control and Carcinogenesis, F045, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: b Pathogenesis of Virus Associated Tumors, F100, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Anatoliy
authors.initials: A
authors.lastname: Shumilov
authors.affiliation: b Pathogenesis of Virus Associated Tumors, F100, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
authors.affiliation: a Cell Cycle Control and Carcinogenesis, F045, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hoffmann
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002877:Chromosomes, Human / Q000378:metabolism; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D019143:Evolution, Molecular; D017353:Gene Deletion; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D011485:Protein Binding; D044843:SKP Cullin F-Box Protein Ligases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004247:DNA; C584002:FBXO28 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D004250:DNA Topoisomerases, Type II
keywords: Cell cycle; F-box protein; Fbxo28; SCF; Topoisomerase IIα; decatenation; mitosis