title: Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A.
abstract: Upon congression at the spindle equator, vertebrate chromosomes display oscillatory movements which typically decline as cells progress towards anaphase. Kinesin-8 Kif18A has been identified as a suppressor of chromosome movements, but how its activity is temporally regulated to dampen chromosome oscillations before anaphase onset remained mysterious. Here, we identify a regulatory network composed of cyclin-dependent kinase-1 (Cdk1) and protein phosphatase-1 (PP1) that antagonistically regulate Kif18A. Cdk1-mediated inhibitory phosphorylation of Kif18A promotes chromosome oscillations in early metaphase. PP1 induces metaphase plate thinning by directly dephosphorylating Kif18A. Chromosome attachment induces Cdk1 inactivation and kinetochore recruitment of PP1α/γ. Thus, we propose that chromosome biorientation mediates the alignment of chromosomes at the metaphase plate by tipping the balance in favour of dephosphorylated Kif18A capable of suppressing the oscillatory movements of chromosomes. Notably, interfering with chromosome oscillations severely impairs the fidelity of sister chromatid segregation demonstrating the importance of timely controlled chromosome dynamics for the maintenance of genome integrity.
authors.affiliation: Department of Molecular Genetics, University of Konstanz, Universitätsstr. 10, 78457 Konstanz, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Häfner
authors.affiliation: Department of Biology, Institute of Biochemistry, ETH Zurich, Schafmattstrasse 18, 8093 Zurich, Switzerland.
authors.forename: Monika I
authors.initials: MI
authors.lastname: Mayr
authors.affiliation: Department of Molecular Genetics, University of Konstanz, Universitätsstr. 10, 78457 Konstanz, Germany.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Möckel
authors.affiliation: Department of Molecular Genetics, University of Konstanz, Universitätsstr. 10, 78457 Konstanz, Germany.
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Mayer
mesh_terms: D000595:Amino Acid Sequence; D000705:Anaphase; D016203:CDC2 Protein Kinase; D002877:Chromosomes, Human / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D012854:Sister Chromatid Exchange; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism
chemical_list: D049452:Green Fluorescent Proteins; D012694:Serine; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D054645:Protein Phosphatase 1; C502735:KIF18A protein, human; D016547:Kinesins