Overcoming inhibition in the spindle checkpoint: Figure 1.

Vanoosthuyse, Vincent; Hardwick, Kevin

doi:10.1101/gad.1882109

Cited by 23 publications

(26 citation statements)

References 57 publications

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“…Silencing the mitotic checkpoint, just like activating the checkpoint, involves events at two venues: at kinetochores and in the cytoplasm (23,46). "Wait anaphase" signals (predominantly C-MAD2) need to be terminated at kinetochores that are fully attached with spindle microtubules and bioriented with tension.…”

Section: Trip13 Is a Novel Mitotic Checkpoint-silencing Protein-mentioning

confidence: 99%

Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) AAA-ATPase Is a Novel Mitotic Checkpoint-silencing Protein

Wang

Sturt-Gillespie

Hittle

et al. 2014

Journal of Biological Chemistry

132

145

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Background: How the mitotic checkpoint is silenced is not fully understood. Results: Interference with TRIP13 AAA-ATPase causes delayed activation of the anaphase-promoting complex/cyclosome and stalled metaphase-to-anaphase transition. Conclusion: TRIP13 is a novel mitotic checkpoint-silencing protein.Significance: TRIP13 overexpression may lead to premature chromosome segregation and chromosomal instability.

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Section: Trip13 Is a Novel Mitotic Checkpoint-silencing Protein-mentioning

confidence: 99%

Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) AAA-ATPase Is a Novel Mitotic Checkpoint-silencing Protein

Wang

Sturt-Gillespie

Hittle

et al. 2014

Journal of Biological Chemistry

132

145

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“…In human cells, checkpoint proteins are stripped from the outer kinetochore upon microtubule attachment and transported to spindle poles in a dynein-dependent fashion [29]. This is thought to be one way vertebrate cells silence the spindle checkpoint, although it is not essential for silencing [30]. However, there is no evidence that dynein is involved in checkpoint protein targeting in yeast mitosis [31].…”

Section: Resultsmentioning

confidence: 99%

Generation of a Spindle Checkpoint Arrest from Synthetic Signaling Assemblies

et al. 2017

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SummaryThe spindle checkpoint acts as a mitotic surveillance system, monitoring interactions between kinetochores and spindle microtubules and ensuring high-fidelity chromosome segregation [1, 2, 3]. The checkpoint is activated by unattached kinetochores, and Mps1 kinase phosphorylates KNL1 on conserved MELT motifs to generate a binding site for the Bub3-Bub1 complex [4, 5, 6, 7]. This leads to dynamic kinetochore recruitment of Mad proteins [8, 9], a conformational change in Mad2 [10, 11, 12], and formation of the mitotic checkpoint complex (MCC: Cdc20-Mad3-Mad2 [13, 14, 15]). MCC formation inhibits the anaphase-promoting complex/cyclosome (Cdc20-APC/C), thereby preventing the proteolytic destruction of securin and cyclin and delaying anaphase onset. What happens at kinetochores after Mps1-dependent Bub3-Bub1 recruitment remains mechanistically unclear, and it is not known whether kinetochore proteins other than KNL1 have significant roles to play in checkpoint signaling and MCC generation. Here, we take a reductionist approach, avoiding the complexities of kinetochores, and demonstrate that co-recruitment of KNL1Spc7 and Mps1Mph1 is sufficient to generate a robust checkpoint signal and prolonged mitotic arrest. We demonstrate that a Mad1-Bub1 complex is formed during synthetic checkpoint signaling. Analysis of bub3Δ mutants demonstrates that Bub3 acts to suppress premature checkpoint signaling. This synthetic system will enable detailed, mechanistic dissection of MCC generation and checkpoint silencing. After analyzing several mutants that affect localization of checkpoint complexes, we conclude that spindle checkpoint arrest can be independent of their kinetochore, spindle pole, and nuclear envelope localization.

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“…p31 comet does not appear to be conserved in all species with Mad2-like proteins (Habu et al 2002), and the involvement of PP1 in checkpoint silencing has only recently been demonstrated in fungi (Pinsky et al 2009;Vanoosthuyse and Hardwick 2009a). Importantly, whether the p31 comet and PP1-dependent mechanisms are sensitive to kinetochoremicrotubule attachment status is currently unclear, and it is possible that these mechanisms operate to limit or inactivate the checkpoint signal in the cytoplasm (Vanoosthuyse and Hardwick 2009b). For PP1, one study has suggested a potential role in dynein-mediated removal of checkpoint proteins (Whyte et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Removal of Spindly from microtubule-attached kinetochores controls spindle checkpoint silencing in human cells

Gassmann

Holland²,

Varma³

et al. 2010

Genes Dev.

183

251

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The spindle checkpoint generates a ''wait anaphase'' signal at unattached kinetochores to prevent premature anaphase onset. Kinetochore-localized dynein is thought to silence the checkpoint by transporting checkpoint proteins from microtubule-attached kinetochores to spindle poles. Throughout metazoans, dynein recruitment to kinetochores requires the protein Spindly. Here, we identify a conserved motif in Spindly that is essential for kinetochore targeting of dynein. Spindly motif mutants, expressed following depletion of endogenous Spindly, target normally to kinetochores but prevent dynein recruitment. Spindly depletion and Spindly motif mutants, despite their similar effects on kinetochore dynein, have opposite consequences on chromosome alignment and checkpoint silencing. Spindly depletion delays chromosome alignment, but Spindly motif mutants ameliorate this defect, indicating that Spindly has a dynein recruitment-independent role in alignment. In Spindly depletions, the checkpoint is silenced following delayed alignment by a kinetochore dynein-independent mechanism. In contrast, Spindly motif mutants are retained on microtubule-attached kinetochores along with checkpoint proteins, resulting in persistent checkpoint signaling. Thus, dynein-mediated removal of Spindly from microtubuleattached kinetochores, rather than poleward transport per se, is the critical reaction in checkpoint silencing. In the absence of Spindly, a second mechanism silences the checkpoint; this mechanism is likely evolutionarily ancient, as fungi and higher plants lack kinetochore dynein. Microtubule attachments of the correct geometry are stabilized by tension experienced at sister kinetochores that have made bioriented connections to opposite poles (Nicklas 1997). Once all kinetochores are attached in a bioriented fashion to microtubule bundles, termed kinetochore fibers, the checkpoint signal is silenced and the cell proceeds to anaphase.The spindle checkpoint regulates the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which targets cyclin B and securin for destruction by the 26S proteasome. Specifically, the checkpoint components Mad2, BubR1, and Bub3 interact with and inhibit the essential APC/C cofactor Cdc20 by forming diffusible mitotic checkpoint complexes (Hwang et al. 1998;Sudakin et al. 2001;Nilsson et al. 2008). Additional components of the checkpoint pathway, including Mad1 and the kinases Bub1 and Mps1, are involved in the generation and amplification of the checkpoint signal (Hoyt et al. 1991;Li and Murray 1991;Abrieu et al. 2001).The conserved KNL-1/Mis12 complex/Ndc80 complex (KMN) network constitutes the core attachment site for microtubules at the kinetochore and also recruits components that generate the checkpoint signal (Burke and Stukenberg 2008). Additional contacts to microtubules are made by the kinesin CENP-E (Weaver et al. 2003) and by the minus end-directed motor dynein and its Cold Spring Harbor Laboratory Press on May 11, 2018 -Published by genesdev.cshlp.org Downloaded from

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Overcoming inhibition in the spindle checkpoint: Figure 1.

Cited by 23 publications

References 57 publications

Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) AAA-ATPase Is a Novel Mitotic Checkpoint-silencing Protein

Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) AAA-ATPase Is a Novel Mitotic Checkpoint-silencing Protein

Generation of a Spindle Checkpoint Arrest from Synthetic Signaling Assemblies

Removal of Spindly from microtubule-attached kinetochores controls spindle checkpoint silencing in human cells

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