Characterization of the Ipl1/Aurora protein kinase in chromosome segregation and the spindle checkpoint

Abstract

The flawless execution of cell division is fundamental to the formation and survival of living organisms. It depends on the accurate and orderly partitioning of chromosomes, resulting in two daughter cells with the correct complement of genetic material. In my research, I sought to understand the role of the Ipl1/Aurora protein kinase in regulating the fidelity of chromosome segregation. This process requires that sister kinetochores bind spindle microtubules arising from opposite poles and come under tension. Furthermore, it requires the function of the spindle checkpoint, a monitoring system that delays cell cycle progression until all chromosomes make proper attachments. I describe here the identification and characterization of the Mtw1/Mis12 kinetochore complex, and show that impairing Ipl1/Aurora function in the mtw1 kinetochore mutant both restores attachment and satisfies the spindle checkpoint. Analysis of a series of kinetochore mutants revealed similar results, suggesting a mechanism to explain how Ipl1/Aurora regulates chromosome segregation. We propose that Ipl1/Aurora responds to the tension defects associated with most kinetochore mutants by destabilizing kinetochore-microtubule interactions and generating unattached kinetochores. These unoccupied microtubule-binding sites then lead to spindle checkpoint activation and eventual correction of the improper attachments. In addition, I examine the mitotic functions of the opposing phosphatase, Glc7/PP1. These studies indicate that Ipl1/Aurora and Glc7/PP1 work in parallel to ensure the accuracy of chromosome segregation by maintaining the balance of phosphorylation on a common set of important targets.