Aurora B potentiates Mps1 activation to ensure rapid checkpoint establishment at the onset of mitosis

Saurin, Adrian T.; Waal, Maike S. van der; Medema, René H.; Lens, Susanne M.A.; Kops, Geert J. P. L.

doi:10.1038/ncomms1319

Cited by 205 publications

(309 citation statements)

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“…We propose that the mutual dependence of Aurora B and Mps1 for the rapid establishment of Aurora B centromere activity and Mps1 kinetochore activity [7] allows for a fast and coordinated start-up of the error correction and mitotic checkpoint machineries so that both processes are fully functional at the point of nuclear envelope breakdown (Fig 4C).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, Aurora B can also directly stimulate the mitotic checkpoint at the onset of mitosis via kinetochore recruitment and subsequent activation of the checkpoint kinase Mps1 [6,7]. Finally, Aurora B may also function further downstream in the mitotic checkpoint signalling cascade to maintain the APC/C inhibitory signal [8].…”

Section: Introductionmentioning

confidence: 99%

“…We allowed cells to enter mitosis without Mps1 activity, using the chemical inhibitors Reversine [15] and Mps1-IN-1 [22], or RNA interference (RNAi)-mediated protein knockdown (Fig 1A,B; supplementary Fig S1A online). Cells were treated with nocodazole to exclude effects of kinetochore-microtubule attachments and, as Mps1 inhibition silences the mitotic checkpoint (supplementary Fig S1C online), we only analysed early prometaphase cells recognized by a dispersed DNA morphology [7].…”

Section: Introductionmentioning

confidence: 99%

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Mps1 promotes rapid centromere accumulation of Aurora B

et al. 2012

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Aurora B localization to mitotic centromeres, which is required for proper chromosome alignment during mitosis, relies on Haspin‐dependent histone H3 phosphorylation and on Bub1‐dependent histone H2A phosphorylation—which interacts with Borealin through a Shugoshin (Sgo) intermediate. We demonstrate that Mps1 stimulates the latter recruitment axis. Mps1 activity enhances H2A‐T120ph and is critical for Sgo1 recruitment to centromeres, thereby promoting Aurora B centromere recruitment in early mitosis. Importantly, chromosome biorientation defects caused by Mps1 inhibition are improved by restoring Aurora B centromere recruitment. As Mps1 kinetochore localization reciprocally depends on Aurora B, we propose that this Aurora B‐Mps1 recruitment circuitry cooperates with the Aurora B‐Haspin feedback loop to ensure rapid centromere accumulation of Aurora B at the onset of mitosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mps1 promotes rapid centromere accumulation of Aurora B

et al. 2012

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“…The components of SAC are conserved from yeast to humans, indicating that this pathway has been consistent throughout evolution. Aurora B kinase and Mps1 are at the top of this pathway and they are thought to regulate each other, [20][21][22][23] the downstream components Bub1, BubR1, Bub3, Mad1 and Mad2 form 3 complexes: Bub1-Bub3, BubR1-Bub3 and Mad1-Mad2. 24 They are recruited to kinetochores in a KMN-dependent manner, [25][26][27] and when the kinetochore is unattached, the checkpoint is activated.…”

Section: Introductionmentioning

confidence: 99%

Cyclin B3 controls anaphase onset independent of spindle assembly checkpoint in meiotic oocytes

Zhang

Huang

et al. 2015

Cell Cycle

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Cyclin B3 is a relatively new member of the cyclin family whose functions are little known. We found that depletion of cyclin B3 inhibited metaphase-anaphase transition as indicated by a well-sustained MI spindle and cyclin B1 expression in meiotic oocytes after extended culture. This effect was independent of spindle assembly checkpoint activity, since both Bub3 and BubR1 signals were not observed at kinetochores in MI-arrested cells. The metaphase I arrest was not rescued by either Mad2 knockdown or cdc20 overexpression, but it was rescued by securin RNAi. We conclude that cyclin B3 controls the metaphase-anaphase transition by activating APC/C cdc20 in meiotic oocytes, a process that does not rely on SAC activity.

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“…The first occurs at NEBD, when Mad1-Mad2 released from nuclear pores is targeted to newly assembled kinetochores by Aurora B [3,31,43]. In the second step, Mad1-Mad2 becomes stably tethered to kinetochores by RZZ, extending SAC surveillance and mitotic arrest more than 10-fold.…”

Section: Discussionmentioning

confidence: 99%

The RZZ complex integrates spindle checkpoint maintenance with dynamic expansion of unattached kinetochores

Rodriguez-Rodriguez

McKinley

Sikirzhytski

et al. 2018

Preprint

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SummaryThe Mad1-Mad2 heterodimer is the catalytic hub of the spindle assembly checkpoint (SAC), which controls mitosis through assembly of a multi-subunit anaphase inhibitor, the mitotic checkpoint complex (MCC) [1,2]. Mad1-Mad2 first catalyzes MCC assembly at interphase nuclear pores [3], then migrates to kinetochores at nuclear envelope breakdown (NEBD) and resumes MCC assembly until bipolar spindle attachment is complete [1,2]. There is significant debate about the factor(s) involved in targeting Mad1-Mad2 to kinetochores in higher eukaryotes [4][5][6][7][8][9]. Through gene editing and livecell imaging, we found that the human Rod-Zw10-Zwilch (RZZ) complex is dispensable for cell viability and initial recruitment of Mad1-Mad2 to kinetochores at NEBD, but then becomes necessary to tether Mad1-Mad2 at kinetochores and sustain SAC arrest in cells challenged with spindle poisons. We also show that RZZ forms the mesh-like fibrous corona, a structural expansion of the outer kinetochore important for timely chromosome congression [10][11][12][13] once Mps1 phosphorylates the N-terminus of Rod.Artificially tethering Mad1-Mad2 to kinetochores enabled long-term mitotic arrest in the absence of RZZ. Conversely, blocking early RZZ-independent recruitment of Mad1-Mad2 eliminated the transient SAC response in RZZ-null cells. We conclude that RZZ drives structural changes in the outer kinetochore that facilitate chromosome biorientation and chronic SAC transduction, a key determinant of cytotoxicity during antimitotic drug therapy [14][15][16].All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/297580 doi: bioRxiv preprint first posted online Apr. 9, 2018; 3 Results RZZ is required for long-term mitotic arrest in response to spindle poisonsRecent studies have reached different conclusions about the specific roles and relative importance of Bub1 and the RZZ complex in targeting Mad1-Mad2 to kinetochores and transducing SAC arrest [4][5][6][7][8]. To interrogate RZZ function with maximum penetrance, we used AAV (adeno-associated virus)-and CRISPR-mediated gene editing to target the KNTC1 (Rod) locus in HCT116 cells, a diploid colorectal cell line ( Fig. S1A-C). The resulting KNTC1 HF/-(hypomorph-flox) cells expressed Rod at ~20% of the wildtype level ( Fig. 1A-B and S1D) and exited mitosis prematurely when microtubule polymerization (nocodazole, 99 ± 6 min s.e.m.) or Eg5-dependent spindle bipolarity (S-trityl-L-cysteine (STLC), 193 ± 9 min s.e.m.) were inhibited, whereas wildtype cells never exited mitosis during the 16-hour timelapse (Fig. 1A-B). To determine if complete loss of the RZZ complex is compatible with clonogenic survival, KNTC1 HF/-cells were transduced with an adenovirus expressing Cre recombinase (AdCre) and subjected to limiting dilution.Unlike most SAC gene knockouts in mammals, KNTC1 -/-cells were viable (Fig. 1...

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Aurora B potentiates Mps1 activation to ensure rapid checkpoint establishment at the onset of mitosis

Cited by 205 publications

References 42 publications

Mps1 promotes rapid centromere accumulation of Aurora B

Mps1 promotes rapid centromere accumulation of Aurora B

Cyclin B3 controls anaphase onset independent of spindle assembly checkpoint in meiotic oocytes

The RZZ complex integrates spindle checkpoint maintenance with dynamic expansion of unattached kinetochores

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