A Cell Biological Perspective on Past, Present and Future Investigations of the Spindle Assembly Checkpoint

Abstract

The spindle assembly checkpoint (SAC) is a quality control mechanism that ensures accurate chromosome segregation during cell division. It consists of a mechanochemical signal transduction mechanism that senses the attachment of chromosomes to the spindle, and a signaling cascade that inhibits cell division if one or more chromosomes are not attached. Extensive investigations of both these component systems of the SAC have synthesized a comprehensive understanding of the underlying molecular mechanisms. This review recounts the milestone results that elucidated the SAC, compiles a simple model of the complex molecular machinery underlying the SAC, and highlights poorly understood facets of the biochemical design and cell biological operation of the SAC that will drive research forward in the near future.

Keywords: aneuploidy; mitosis; signal transduction; spindle assembly checkpoint.

Figure 1

Schematic of the overall design of the spindle assembly checkpoint (SAC).

Figure 2

(a) Cartoon depicting the three-component microtubule-sensing mechanism in a kinetochore that lacks end-on microtubule attachment. (b) Microtubule attachment disrupts SAC signaling via two distinct mechanisms. The cartoons depict 1D visualization of the budding yeast kinetochore [66]. The green shape represents the Dam1 ring found in budding yeast; the blue rod like molecule is the Mtw1/Mis12 complex. Top: end-on attachment dislodges a large fraction of the Mps1 from the kinetochore. Bottom: End-on attachment separates the Calponin-Homology domains and the phosphodomain of Spc105/KNL1 from each other. (c) A simplified schematic of the biochemical interaction network that recruits SAC proteins to the unattached kinetochore. Black arrows represent binding to proteins localized in the kinetochore. Gray arrow indicates a conformational change that converts inactive Mad2 (also known as “Open” Mad2) into its active form (“Closed” Mad2).