Topoisomerase II SUMOylation activates a metaphase checkpoint via Haspin and Aurora B kinases
| Autor: | Makoto Michael Yoshida, Victoria A. Hassebroek, Nootan Pandey, Caitlin Soroka, Daniel Keifenheim, Yoshiaki Azuma, Duncan J. Clarke |
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| Rok vydání: | 2019 |
| Předmět: |
Protein sumoylation
Cell cycle checkpoint SUMO protein Aurora B kinase Mitosis Diketopiperazines Protein Serine-Threonine Kinases Biology Piperazines Article 03 medical and health sciences 0302 clinical medicine Chromosome Segregation Aurora Kinase B Chromosomes Human Humans Topoisomerase II Inhibitors Phosphorylation Kinetochores Metaphase Research Articles 030304 developmental biology Anaphase 0303 health sciences Kinetochore Intracellular Signaling Peptides and Proteins Sumoylation Cell Biology Cell biology DNA Topoisomerases Type II 030220 oncology & carcinogenesis biological phenomena cell phenomena and immunity HeLa Cells |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | To prevent chromosome missegregation, a metaphase checkpoint is activated when topoisomerase II is catalytically inhibited and DNA catenations persist. Pandey et al. dissect the key molecular events triggering this regulatory system. Topoisomerase II (Topo II) is essential for mitosis since it resolves sister chromatid catenations. Topo II dysfunction promotes aneuploidy and drives cancer. To protect from aneuploidy, cells possess mechanisms to delay anaphase onset when Topo II is perturbed, providing additional time for decatenation. Molecular insight into this checkpoint is lacking. Here we present evidence that catalytic inhibition of Topo II, which activates the checkpoint, leads to SUMOylation of the Topo II C-terminal domain (CTD). This modification triggers mobilization of Aurora B kinase from inner centromeres to kinetochore proximal centromeres and the core of chromosome arms. Aurora B recruitment accompanies histone H3 threonine-3 phosphorylation and requires Haspin kinase. Strikingly, activation of the checkpoint depends both on Haspin and Aurora B. Moreover, mutation of the conserved CTD SUMOylation sites perturbs Aurora B recruitment and checkpoint activation. The data indicate that SUMOylated Topo II recruits Aurora B to ectopic sites, constituting the molecular trigger of the metaphase checkpoint when Topo II is catalytically inhibited. |
| Databáze: | OpenAIRE |
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