Cell Division: SACing the Anaphase Problem
| Autor: | Geert J. P. L. Kops |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Male
Cell cycle checkpoint Agricultural and Biological Sciences(all) Kinetochore Biochemistry Genetics and Molecular Biology(all) Biology General Biochemistry Genetics and Molecular Biology Sister chromatid segregation Cell biology Chromosome segregation Anaphase lag Spindle checkpoint Securin Report CDC2 Protein Kinase Animals Humans M Phase Cell Cycle Checkpoints Female biological phenomena cell phenomena and immunity General Agricultural and Biological Sciences Anaphase Kinetochores |
| Zdroj: | Current Biology |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/j.cub.2014.02.020 |
| Popis: | Summary 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/CCdc20) [2]. Upon satisfaction of both pathways, the APC/CCdc20 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/CCdc20 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/CCdc20 couples chromosome segregation to the dissolution of attachment monitoring mechanisms during mitotic exit. Graphical Abstract Highlights • Cyclin B degradation stabilizes kinetochore attachments in anaphase • Cdk1 inactivation prevents mitotic checkpoint engagement after anaphase onset • Chromatid disjunction by separase causes APC/C inhibition if Cdk1 remains active • APC/C links separase activation to dissolution of attachment monitoring mechanisms Vázquez-Novelle et al. propose that Cdk1-cyclin B activity sets the temporal window for microtubule-kinetochore attachment surveillance. Failure to degrade cyclin B at anaphase onset destabilizes attachments and engages the mitotic checkpoint. APC/C-induced proteolysis could couple sister chromatid disjunction to checkpoint dissolution when sister chromatids split. |
| Databáze: | OpenAIRE |
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