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Principles and dynamics of spindle assembly checkpoint signalling

Nature Reviews Molecular Cell Biology volume 24, pages 543–559 (2023)Cite this article

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Abstract

The transmission of a complete set of chromosomes to daughter cells during cell division is vital for development and tissue homeostasis. The spindle assembly checkpoint (SAC) ensures correct segregation by informing the cell cycle machinery of potential errors in the interactions of chromosomes with spindle microtubules prior to anaphase. To do so, the SAC monitors microtubule engagement by specialized structures known as kinetochores and integrates local mechanical and chemical cues such that it can signal in a sensitive, responsive and robust manner. In this Review, we discuss how SAC proteins interact to allow production of the mitotic checkpoint complex (MCC) that halts anaphase progression by inhibiting the anaphase-promoting complex/cyclosome (APC/C). We highlight recent advances aimed at understanding the dynamic signalling properties of the SAC and how it interprets various naturally occurring intermediate attachment states. Further, we discuss SAC signalling in the context of the mammalian multisite kinetochore and address the impact of the fibrous corona. We also identify current challenges in understanding how the SAC ensures high-fidelity chromosome segregation.

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Fig. 1: Kinetochore attachment states and SAC signalling.
Fig. 2: SAC proteins orchestrate the generation of MCCs to delay anaphase.
Fig. 3: Corona expansion and SAC silencing mechanisms.
Fig. 4: Disassembling the anaphase inhibitor.
Fig. 5: Mechanochemical model for SAC silencing.
Fig. 6: Different models to explain SAC silencing at ‘ensemble’ kinetochores.
Fig. 7: SAC signalling properties at kinetochores.

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Acknowledgements

The authors thank S. Biggins and J. Millar for comments on the manuscript, C. Conway for helping devise Fig. 7a  and the three reviewers for their thorough and constructive feedback. A.D.M. is supported by a Wellcome collaborator award (215625) and the Biotechnology and Biological Sciences Research Council (BB/R009503/1).

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Authors and Affiliations

  1. Centre for Mechanochemical Cell Biology, University of Warwick, Coventry, UK

    Andrew D. McAinsh

  2. Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK

    Andrew D. McAinsh

  3. Hubrecht Institute — KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Centre Utrecht, Utrecht, The Netherlands

    Geert J. P. L. Kops

  4. Oncode Institute, Utrecht, The Netherlands

    Geert J. P. L. Kops

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Glossary

AAA+ ATPase

A class of protein enzymes that use ATP hydrolysis for remodelling or translocating macromolecules.

Aneuploidy

The state where a cell of a given species has numerous chromosomes that deviates from a multiple of the haploid set of that species.

Centromeric chromatin

Specialized chromatin at centromeres that define the site of kinetochore assembly, in which a subset of nucleosomes contains the histone H3 variant centromere protein A (CENP-A).

Chromosome bi-orientation

The configuration of a duplicated chromosome on a bipolar spindle in mitosis in which the kinetochore of one sister chromatid is attached to one pole whereas the kinetochore of the other sister chromatid is attached to the other pole.

Chromosomal passenger complex

(CPC). A tetrameric protein complex containing the Aurora B kinase that locates to and functions at various locations in mitotic cells, regulating sister chromatid cohesion, attachment error correction, spindle checkpoint signalling and cytokinesis.

Degron

A short linear amino acid sequence motif that is recognized by the cellular protein degradation machinery for targeting the host protein for degradation.

End-on interactions

Interactions of kinetochore proteins with microtubules near their plus ends, resulting in plus-end embedding into kinetochores and subsequent ability of plus-end depolymerization to exert pulling force on the chromosome.

Holocentric chromosomes

Chromosomes, natural to certain species, that contain microtubule-binding kinetochores along their entire length rather than at a single defined location (that is, the centromere).

Interphase

The phase between two mitosis events, encompassing the cell cycle phases G0, G1, S and G2.

Kinetochore fibres

Bundles of microtubules that together connect to a single kinetochore.

NDC80 complex

A tetrameric protein complex assembled from SPC24, SPC25, NUF2 and NDC80 (also known as HEC1), of which the latter two components directly bind to microtubules.

Nuclear envelope breakdown

The process of disassembling the nuclear envelope at the start of mitosis in order to enable access of chromosomes to cytoplasmic microtubules.

Paralogues

Pairs of homologous genes that have diverged in sequence following gene duplication during evolution.

Spindle poles

The regions of the spindle where the minus ends of microtubules come together. In human somatic cells, the centrosomes form the two spindle poles.

Taxol

Brand name of paclitaxel, a cytostatic anticancer drug that inhibits microtubule depolymerization, originally made from extract of the Taxus brevifolia tree.

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McAinsh, A.D., Kops, G.J.P.L. Principles and dynamics of spindle assembly checkpoint signalling. Nat Rev Mol Cell Biol 24, 543–559 (2023). https://doi.org/10.1038/s41580-023-00593-z

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