For each chromosome to properly segregate during mitosis, its kinetochores must bipolarly attach spindle microtubules. The failure of chromosomes to biorient is a major cause of cellular aneuploidy, a driving force in cancer and birth defects. Bipolar attachment is achieved because tension is produced between sister kinetochores, which both stabilizes microtubule attachments and turns off spindle checkpoint signals. The key to understanding how cells become aneuploid is to understand how chromosomes sense tension between sister kinetochores and use this to regulate microtubule attachment and spindle checkpoint signals. Recently we and others have implicated three components in this process-the Aurora B kinase complex, the MCAK microtubule depolymerase and the Polo kinase. We have published that the Aurora B regulates MCAK activity in centromeres presumably to release improperly attached microtubules, while Polo kinase phosphorylates proteins in the kinetochore in response to the lack of tension. We present new data that MCAK localization and activity is tightly controlled and the each chromosome regulates MCAK autonomously. Moreover we demonstrate that there is a network of interactions between five centromere proteins to regulate MCAK activity and localization including Aurora B and Polo kinases, the Gunanine Nucleotide Exchange Factor, TD-60, and the MCAK activator, ICIS. To elucidate the mechanisms that prevent aneuploidy, the experiments in this proposal dissect the molecular mechanisms of the centromere signaling network. ? ?
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