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Topoisomerase II SUMOylation activates a metaphase checkpoint via Haspin and Aurora B kinases
Pandey, Nootan Keifenheim, Daniel Yoshida, Makoto Michael Hassebroek, Victoria A. Soroka, Caitlin Azuma, Yoshiaki Clarke, Duncan J.
Pandey, Nootan
Keifenheim, Daniel
Yoshida, Makoto Michael
Hassebroek, Victoria A.
Soroka, Caitlin
Azuma, Yoshiaki
Clarke, Duncan J.
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Abstract
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.
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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Date
2019-11-11
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Rockefeller University Press
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Keywords
Cancer, Cell cycle and division, Chromatin or epigenetics
Citation
Nootan Pandey, Daniel Keifenheim, Makoto Michael Yoshida, Victoria A. Hassebroek, Caitlin Soroka, Yoshiaki Azuma, Duncan J. Clarke; Topoisomerase II SUMOylation activates a metaphase checkpoint via Haspin and Aurora B kinases. J Cell Biol 6 January 2020; 219 (1): e201807189. doi: https://doi.org/10.1083/jcb.201807189