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We use combined molecular and genetic experimental strategies to decipher the molecular structure and mechanism of action of the centromere/kinetochore, the macromolecular structure responsible for attachment of chromosomes to the mitotic spindle during cell division. As experimental organisms, we use several budding and fission yeasts (Saccharomyces cerevisiae and Schizosaccharomyces pombe), plus two pathogenic fungi, Candida albicans and Candida glabrata, with the goal of identifying specific targets for antifungal chemotherapy. In the yeasts, the chromosomes and associated kinetochores are smaller and more easily analyzed than their counterparts in animal cells, and powerful genetic analysis and DNA transformation systems can be employed. In collaboration with Professor Louise Clarke, we have isolated and characterized functional centromere DNAs from both budding and fission yeasts. These centromeric DNA sequences (CEN) can be used to construct functional artificial chromosomes (YAC's) that segregate properly in transformed host cells. YAC's are valuable experimental models to study the mechanism of chromosome maintenance and transmission, and are used in laboratories worldwide as vectors for the cloning in yeast of very large segments of genomic DNA. A total of 11 kinetochore proteins associated with the CEN region have now been identified. These kinetochore proteins mediate attachment of the CEN DNA to the microtubules near the plus ends, and regulate assembly and disassembly of the microtubule polymer as the chromosome moves on the spindle. In the Carbon, Wilson, Clarke, and Lew laboratories, a large number of graduate students, postdoctoral fellows and professional researchers are actively investigating mitosis, microtubules and molecular motors.
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