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Constitutive Mad1 targeting to kinetochores uncouples checkpoint signalling from chromosome biorientation

2011; Nature Portfolio; Volume: 13; Issue: 4 Linguagem: Inglês

10.1038/ncb2223

1476-4679

María Maldonado, Tarun M. Kapoor,

Protist diversity and phylogeny

Targeting Mad1 to kinetochores reveals that Mad1 localization is sufficient to induce mitotic-checkpoint-dependent arrest, and that Aurora B, Mps1 and BubR1 are required for checkpoint maintenance. Accurate chromosome segregation depends on biorientation, whereby sister chromatids attach to microtubules from opposite spindle poles. The spindle-assembly checkpoint is a surveillance mechanism in eukaryotes that inhibits anaphase until all chromosomes have bioriented1,2,3. In present models, the recruitment of the spindle-assembly checkpoint protein Mad2, through Mad1, to non-bioriented kinetochores is needed to stop cell-cycle progression3,4,5,6. However, it is unknown whether Mad1–Mad2 targeting to kinetochores is sufficient to block anaphase. Furthermore, it is unclear whether regulators of biorientation (for example, Aurora kinases7) have checkpoint functions downstream of Mad1–Mad2 recruitment or whether they act upstream to quench the primary error signal8. Here, we engineered a Mad1 construct that localizes to bioriented kinetochores. We show that the kinetochore localization of Mad1 is sufficient for a metaphase arrest that depends on Mad1–Mad2 binding. By uncoupling the checkpoint from its primary error signal, we show that Aurora, Mps1 and BubR1 kinases, but not Polo-like kinase, are needed to maintain checkpoint arrest when Mad1 is present on kinetochores. Together, our data suggest a model in which the biorientation errors, which recruit Mad1–Mad2 to kinetochores, may be signalled not only through Mad2 template dynamics9, but also through the activity of widely conserved kinases, to ensure the fidelity of cell division.