Mechanisms underlying chromosome segregation

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Project Summary Accurate cell division is essential for the development of all organisms. During each cell cycle, chromosomes must be precisely partitioned to daughter cells. Defects in chromosome partitioning generate aneuploidy, the state where entire chromosomes are gained or loss. Aneuploidy is a the most common chromosomal abnormality in cancer cells and is thought to be a major factor in the evolution of cancer. It is also the leading cause of miscarriages and hereditary birth defects in humans. The proposed work will lead to an understanding of the mechanisms that ensure accurate chromosome partitioning. This work is important for maintaining genomic stability and preventing human disease. Chromosome partitioning occurs when spindle microtubules move chromosomes by interacting with kinetochores, the machines that assemble onto the chromosome at a locus called the centromere. Kinetochores carry out a number of functions, such as maintaining load-bearing attachments to the ends of microtubules that are continually growing and shrinking. They also control the cell cycle when there is a defect in kinetochore attachments to microtubules. Our lab will address two fundamental questions about chromosome segregation using in vitro assays: 1) How is kinetochore assembly regulated? 2) How do kinetochore proteins contribute to force-dependent kinetochore-microtubule attachments? We will use budding yeast for these studies because they are amenable to biochemical, genetic and cytological studies, and the yeast kinetochore is the best characterized to date. Taken together, our work will lead toward an understanding of the fundamental mechanisms of chromosome partitioning in all eukaryotes.