The spindle checkpoint

Every mitosis, replicated chromosomes must be accurately segregated into each daughter cell. Pairs of sister chromatids attach to the bipolar mitotic spindle during prometaphase, they are aligned at metaphase, then sisters separate and are pulled to opposite poles during anaphase. Failure to attach correctly to the spindle before anaphase onset results in unequal segregation of chromosomes, which can lead to cell death or disease. The spindle checkpoint is a surveillance mechanism that delays anaphase onset until all chromosomes are correctly attached in a bipolar fashion to the mitotic spindle. The core spindle checkpoint proteins are Mad1, Mad2, BubR1 (Mad3 in yeast), Bub1, Bub3 and Mps1. The Mad and Bub proteins were first identified in budding yeast by genetic screens for mutants that failed to arrest in mitosis when the spindle was destroyed (Taylor et al., 2004). These proteins are conserved in all eukaryotes. Several other checkpoint components, such as Rod, Zw10 and CENP-E, have since been identified in higher eukaryotes but have no yeast orthologues (Karess, 2005; Mao et al., 2003). This reflects a more complex checkpoint regulation in higher eukaryotes where, unlike in yeasts, checkpoint proteins are essential and regulate normal mitotic timing (Meraldi et al., 2004; Taylor et al., 2004). Here, we highlight current understanding of how the spindle checkpoint is activated, how it delays anaphase onset, and how it is silenced. Activation of the checkpoint During mitosis spindle microtubules bind to complex protein structures called kinetochores, which assemble on the centromere of each chromosome. The Mad and Bub proteins localise to the outer kinetochore early in mitosis, before proper attachments are established, and accumulate on unattached kinetochores. When spindle microtubules make contact with the outer kinetochore a number of complex molecular interactions take place that regulate both attachment and microtubule dynamics (Maiato et al., 2004). The checkpoint proteins are therefore ideally placed to monitor these interactions