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The spindle-assembly checkpoint in space and time

Key Points

  • The spindle-assembly checkpoint (SAC) is a safety device that monitors the attachment of spindle microtubules to the surface of chromosome-associated structures called kinetochores. It is believed that the SAC senses the occupancy of microtubules at the surface of kinetochores, as well as the accumulation of inter-kinetochore tension when sister kinetochores are linked to opposite spindle poles.

  • The SAC is active in prometaphase during the microtubule–kinetochore attachment process, and it is downregulated when all sister chromatids have aligned to the mitotic spindle in a bipolar fashion. This triggers the loss of sister-chromatid cohesion, which initiates sister-chromatid separation at anaphase.

  • The signalling activity of the SAC in prometaphase seems to converge on the formation of at least one SAC effector, the mitotic checkpoint complex (MCC). This complex contains the SAC proteins MAD2, BUBR1 and BUB3 bound to the SAC target CDC20. This complex inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C), which is required to remove sister-chromatid cohesion.

  • The way the MCC is generated from its constituent subunits is the subject of controversy. Especially controversial is the relative contribution offered by the cytosol and by kinetochores to MCC formation. There is evidence from Saccharomyces cerevisiae that the MCC can form in the absence of kinetochores. On the other hand, all SAC proteins localize to kinetochores in mitosis and it seems likely that this will contribute a mass-action effect, enhancing the rate of MCC formation.

  • A still-speculative hypothesis, the 'MAD2 template' hypothesis, proposes that the interaction of MAD2 with CDC20 follows a prion-like scenario in which an O-MAD2 conformer is primed by a kinetochore-bound C-MAD2 conformer to bind CDC20.

  • Besides the core SAC machinery, which is represented by the MCC subunits, several auxiliary functions contribute to SAC signal amplification. These include certain kinases (BUB1, BUBR1, MPS1 and Aurora B), the microtubule motor protein centromere protein E (CENP-E), and components of the ROD–ZW10–ZWILCH (RZZ) complex. p31comet and dynein, on the other hand, contribute to the downregulation of SAC signalling.

  • Subtle alterations of SAC function might cause aneuploidy and accelerate tumorigenesis. On the other hand, the SAC is an essential device in metazoans, and current evidence indicates that its functions are also essential for the survival of cancer cells. This points to the SAC as a possible target in cancer therapy.

Abstract

In eukaryotes, the spindle-assembly checkpoint (SAC) is a ubiquitous safety device that ensures the fidelity of chromosome segregation in mitosis. The SAC prevents chromosome mis-segregation and aneuploidy, and its dysfunction is implicated in tumorigenesis. Recent molecular analyses have begun to shed light on the complex interaction of the checkpoint proteins with kinetochores — structures that mediate the binding of spindle microtubules to chromosomes in mitosis. These studies are finally starting to reveal the mechanisms of checkpoint activation and silencing during mitotic progression.

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Figure 1: Domain organization of SAC proteins.
Figure 2: Relationship of the SAC with the cell-cycle machinery.
Figure 3: The attachment process.
Figure 4: The centromere–kinetochore region.
Figure 5: Model for the molecular basis of SAC function.
Figure 6: 'Feedback' pathways in the SAC network.

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Acknowledgements

We thank S. Piatti and members of the Musacchio and Salmon laboratories for critical reading of the manuscript and helpful discussions. Research in the Musacchio laboratory is funded by the Association for International Cancer Research (AICR), the Telethon Foundation, the EU FP6 programme contracts 3D-Repertoire and Mitocheck, the Italian Association for Cancer Research (AIRC), the Fondo di Investimento per la Ricerca di Base (FIRB), the Italian Ministry of Health, the Fondazione Cariplo and the Human Frontier Science Program. Research in the Salmon laboratory is funded by grants from the US National Institutes of Health and the Human Frontier Science Program. We deeply apologize to all colleagues whose work could not be cited owing to space limitations.

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DATABASES

Interpro

HORMA

Saccharomyces genome database

BUB1

BUB3

Ipl1

Kar3

MAD1

MAD2

MAD3

Ndc10

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Glossary

Anaphase-promoting complex/cyclosome

(APC/C). A multiprotein complex with ubiquitin-ligase activity that is responsible for the ubiquitylation of several key cell-cycle regulators, including cyclin B and securin. Also known as the cyclosome.

26S proteasome

A multiprotein complex endowed with protease activity. It is responsible for the proteolytic degradation of substrates tagged by polyubiquitin chains, including those created by the APC/C.

Mitotic checkpoint complex

(MCC). A complex that contains the APC/C activator CDC20 and the spindle-assembly checkpoint proteins MAD2, BUBR1/Mad3 and BUB3. The MCC is regarded as the effector of the spindle-assembly checkpoint.

Kinetochore

A large protein assembly that mediates the attachment of chromosomes to spindle microtubules. Kinetochores assemble, specifically during mitosis, around specialized chromosomal regions known as centromeres, and disassemble at the end of mitosis.

Monotelic attachment

A condition in which only one sister kinetochore in a pair of sister kinetochores is attached to kinetochore microtubules. Monotelic attachment is a normal stage during the process of microtubule–kinetochore attachment and chromosome bi-orientation in prometaphase. The unattached kinetochore of a mono-orientated chromosome is a potent checkpoint signal.

Histone variant

A non-allelic variant of the histone proteins that has specific expression and localization patterns.

Syntelic attachment

A type of incorrect microtubule–kinetochore attachment in which both sister kinetochores become attached to microtubules from the same spindle pole. Syntelically attached kinetochores often reside near a pole and do not congress to the spindle equator. The correction of syntelic attachment requires the Aurora-B/Ipl1 kinase.

Merotelic attachment

A type of incorrect microtubule–kinetochore attachment in which a kinetochore becomes attached to microtubules from both spindle poles. Merotelic attachment by one sister kinetochore does not prevent chromosome bi-orientation by monotelic attachment of the other sister kinetochore and it does not activate the spindle-assembly checkpoint. However, a mechanism of correction based on the Aurora-B/Ipl1 kinase exists.

KEN-box motif

A sequence motif (KENXXXN) that is present in several substrates of the APC/C.

Fluorescence recovery after photobleaching

(FRAP). An imaging technique that measures the kinetics and extent of fluorescence recovery in small volumes that have been subjected to a short high-energy laser pulse to irreversibly bleach a fluorophore. The recovery curves measure labelled-protein diffusion rates in the cytosol and dissociation rate constants from binding sites.

Chromosomal passenger complex

(CPC). A protein complex that shares a characteristic pattern of association with chromatin in prophase, centromeres in metaphase and early anaphase, and the midzone and midbody in late anaphase and telophase, respectively.

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Musacchio, A., Salmon, E. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8, 379–393 (2007). https://doi.org/10.1038/nrm2163

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