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. The mechanisms underlying spindle checkpoint signalling at the kinetochore, which ensures faithful chromosome segregation during cell division, are being unravelled. They indicate that the checkpoint response is graded rather than switch-like (completely on or off) as traditionally thought, and provide insights for the treatment of cancers in which the checkpoint is bypassed. 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.