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Nat Commun. 2018 Oct 19;9(1):4354. doi: 10.1038/s41467-018-06774-1.

TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC.

Author information

1
Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, CA, 92093, USA.
2
Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA, 92093, USA.
3
Center for Genomic Integrity, Institute for Basic Science (IBS), Ulsan, 44919, Republic of Korea.
4
Ionis Pharmaceuticals, 2855 Gazelle Ct, Carlsbad, CA, 92010, USA.
5
School of Life Sciences, Ulsan National Institute for Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
6
Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA, 92093, USA. kcorbett@ucsd.edu.
7
Department of Chemistry, University of California-San Diego, La Jolla, CA, 92093, USA. kcorbett@ucsd.edu.
8
Ludwig Institute for Cancer Research, San Diego Branch, La Jolla, CA, 92093, USA. dcleveland@ucsd.edu.
9
Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA, 92093, USA. dcleveland@ucsd.edu.

Abstract

The mitotic checkpoint ensures accurate chromosome segregation through assembly of the mitotic checkpoint complex (MCC), a soluble inhibitor of the anaphase-promoting complex/cyclosome (APC/C) produced by unattached kinetochores. MCC is also assembled during interphase by Mad1/Mad2 bound at nuclear pores, thereby preventing premature mitotic exit prior to kinetochore maturation and checkpoint activation. Using degron tagging to rapidly deplete the AAA+ ATPase TRIP13, we show that its catalytic activity is required to maintain a pool of open-state Mad2 for MCC assembly, thereby supporting mitotic checkpoint activation, but is also required for timely mitotic exit through catalytic disassembly of MCC. Strikingly, combining TRIP13 depletion with elimination of APC15-dependent Cdc20 ubiquitination/degradation results in a complete inability to exit mitosis, even when MCC assembly at unattached kinetochores is prevented. Thus, mitotic exit requires MCC produced either in interphase or mitosis to be disassembled by TRIP13-catalyzed removal of Mad2 or APC15-driven ubiquitination/degradation of its Cdc20 subunit.

PMID:
30341343
PMCID:
PMC6195577
DOI:
10.1038/s41467-018-06774-1
[Indexed for MEDLINE]
Free PMC Article

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