Deregulation of factors needed for accurate chromosome segregation can result in aneuploidy, a significant contributor to cancer etiology. Equal division of a replicated genome requires that sister chromatids migrate to opposite poles of the mitotic spindle in anaphase: segregation fidelity relies on elaborate mechanics and is dependent on proper chromosome organization. Factors involved in chromosome condensation and genome orgatization are also critical for maintaining genome stability. Together, genome instability and aneuploidy are key factors in malignant progression. Known proteins involved in chromosome architecture are highly conserved between humans and budding yeast (S. cerevisiae). However, many factors involved in these processes remain to be isolated. Since yeasts are genetically tractable, they provide ideal systems in which novel factors required for cellular process can be rapidly identified. Our goal is to identify and understand new budding yeast proteins that control the dynamics of chromosome organization and structure through the cell cycle. Our hypothesis is that human homologs of these proteins will be required to maintain the fidelity of chromosome segregation and the integrity of the genome. These factors will therefore be relevant to the etiology of cancer. Yeast genetic screens will be used to isolate novel mutants defective in chromosome condensation. Two green fluorescent protein (GFP)-tagged chromosome loci, separated by -10-50 kilobases of DNA are visualized as a single discrete fluorescence signal in yeast cells. However, mutants that affect chromosome condensation states will allow the tagged loci to be discerned from one another by fluorescence microscopy. Other phenotypes, such as reduced signal intensity, are also expected in many condensation mutants. Based on these phenotypes, mutants affecting chromosome organization will be identified, both by visual inspection and a combination of automated microscopy and computer-aided diagnosis.
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