The spindle-assembly checkpoint in space and time

• Published in: Nature reviews. Molecular cell biology Vol. 8; no. 5; pp. 379 - 393
• Main Authors: Musacchio, Andrea, Salmon, Edward D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2007; Nature Publishing Group
• Subjects: Aneuploidy; Animals; Biochemistry; Biomedical and Life Sciences; Cancer Research; Carcinogenesis; Cell Biology; Cell Cycle - physiology; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Chromosomes; Developmental Biology; Genes; Genes, cdc - physiology; Humans; Kinases; Kinetochores - physiology; Life Sciences; Microtubules; Mitosis; Models, Biological; Neoplasms - etiology; Neoplasms - genetics; Oncology; Phosphotransferases - physiology; Physiological aspects; Proteins; review-article; Safety devices; Spindle Apparatus - metabolism; Stem Cells; Time Factors; Italy
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm2163

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. p31 comet 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. The spindle-assembly checkpoint is a safety device that monitors the attachment of spindle microtubules to kinetochores and ensures the fidelity of chromosome segregation in mitosis. Molecular studies are finally starting to reveal the mechanisms of checkpoint activation and inactivation. 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.