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Signalling dynamics in the spindle checkpoint response

Key Points

  • The spindle checkpoint signalling cascade prevents anaphase onset until all chromosomes are correctly attached, through their kinetochores, to spindle microtubules.

  • Molecular interactions between kinetochore and spindle checkpoint proteins have been defined and characterized.

  • There have been significant advances in understanding the molecular details of phosphoregulation and checkpoint scaffolding.

  • Monopolar spindle protein 1 (MPS1) has emerged as a direct activating kinase of the checkpoint.

  • The checkpoint response strength is variable and corresponds with the number of unattached kinetochores.

  • Inactivation of cyclin-dependent kinase 1 (CDK1) by cyclin B degradation is a basis for checkpoint inactivation during anaphase.

  • Nuclear pore complexes, in addition to kinetochores, signal the checkpoint.

Abstract

The spindle checkpoint ensures proper chromosome segregation during cell division. Unravelling checkpoint signalling has been a long-standing challenge owing to the complexity of the structures and forces that regulate chromosome segregation. New reports have now substantially advanced our understanding of checkpoint signalling mechanisms at the kinetochore, the structure that connects microtubules and chromatin. In contrast to the traditional view of a binary checkpoint response — either completely on or off — new findings indicate that the checkpoint response strength is variable. This revised perspective provides insight into how checkpoint bypass can lead to aneuploidy and informs strategies to exploit these errors for cancer treatments.

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Figure 1: Kinetochore–microtubule attachment states on the mitotic spindle.
Figure 2: Kinetochore activation of the checkpoint through hierarchical checkpoint protein recruitment.
Figure 3: Checkpoint protein regions and interactions.
Figure 4: Possible spindle checkpoint silencing mechanisms at the kinetochore.
Figure 5: The graded checkpoint response.
Figure 6: Control of the timing of checkpoint signalling.

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Acknowledgements

The authors are grateful to the reviewers and M. Miller for thoughtful comments on the manuscript and apologize to those who were not cited owing to space limitations. N.L. was supported by a US National Institutes of Health (NIH) centre interdisciplinary training grant (T32 CA080416), and work in the Biggins laboratory is supported by NIH grants GM064386 and GM078069 to S.B.

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Glossary

Bi-oriented

The kinetochore–microtubule attachment state where sister kinetochores are attached exclusively to opposite spindle poles by similar numbers of microtubules.

Cohesin complex

A protein complex that physically links DNA on sister or homologous chromosomes following S-phase and that must be cleaved for mitotic progression.

E3 ubiquitin ligase

Enzyme responsible for transfer of ubiquitin to substrates, often targeting them for degradation by the proteasome. E3 ligases transfer ubiquitin from E2 enzymes to their substrates.

Pseudokinase

A protein that is evolutionarily derived from an active kinase that has lost catalytic activity.

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London, N., Biggins, S. Signalling dynamics in the spindle checkpoint response. Nat Rev Mol Cell Biol 15, 736–748 (2014). https://doi.org/10.1038/nrm3888

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