title: Cdk1 inactivation terminates mitotic checkpoint surveillance and stabilizes kinetochore attachments in anaphase.
abstract: Two mechanisms safeguard the bipolar attachment of chromosomes in mitosis. A correction mechanism destabilizes erroneous attachments that do not generate tension across sister kinetochores [1]. In response to unattached kinetochores, the mitotic checkpoint delays anaphase onset by inhibiting the anaphase-promoting complex/cyclosome (APC/C(Cdc20)) [2]. Upon satisfaction of both pathways, the APC/C(Cdc20) elicits the degradation of securin and cyclin B [3]. This liberates separase triggering sister chromatid disjunction and inactivates cyclin-dependent kinase 1 (Cdk1) causing mitotic exit. How eukaryotic cells avoid the engagement of attachment monitoring mechanisms when sister chromatids split and tension is lost at anaphase is poorly understood [4]. Here we show that Cdk1 inactivation disables mitotic checkpoint surveillance at anaphase onset in human cells. Preventing cyclin B1 proteolysis at the time of sister chromatid disjunction destabilizes kinetochore-microtubule attachments and triggers the engagement of the mitotic checkpoint. As a consequence, mitotic checkpoint proteins accumulate at anaphase kinetochores, the APC/C(Cdc20) is inhibited, and securin reaccumulates. Conversely, acute pharmacological inhibition of Cdk1 abrogates the engagement and maintenance of the mitotic checkpoint upon microtubule depolymerization. We propose that the simultaneous destruction of securin and cyclin B elicited by the APC/C(Cdc20) couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit.
authors.affiliation: Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, UK. Electronic address: lolavazquez.novelle@cancer.org.uk.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Vázquez-Novelle
authors.affiliation: Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Laurent
authors.initials: L
authors.lastname: Sansregret
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
authors.forename: Amalie E
authors.initials: AE
authors.lastname: Dick
authors.affiliation: Centre for Mechanochemical Cell Biology, Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Smith
authors.affiliation: Centre for Mechanochemical Cell Biology, Division of Biomedical Cell Biology, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McAinsh
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Gerlich
authors.affiliation: Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire EN6 3LD, UK. Electronic address: mark.petronczki@cancer.org.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: Petronczki
mesh_terms: D000705:Anaphase / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000502:physiology*; D002842:Chromatids / Q000502:physiology; D019926:Cyclin B / Q000502:physiology; D056744:Cyclin B1 / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000502:physiology*; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D009630:Nondisjunction, Genetic / Q000502:physiology; D064247:Separase / Q000502:physiology
chemical_list: D019926:Cyclin B; D056744:Cyclin B1; D016203:CDC2 Protein Kinase; D064247:Separase