Chromosome instability (CIN) due to genetic perturbation in cancer cells is now widely recognized tobe a major predisposing condition in cancer initiation and/or progression. The general objective ofthis proposal is to identify and characterize the molecular components required for mitoticchromosome transmission fidelity in yeast and to identify cognate components in mammalian species.
The specific aims are:1). To identify all genes that are mutable to a CIN phenotype, including both essential and nonessentialfunctions. Three independent screens that monitor instability of a chromosomal marker willbe used to identify a comprehensive set of proteins that are important for the preservation of genomestability. The corresponding gene sets will be annotated, cross-checked, and compared.2). To establish genetic interaction maps for CIN genes mutated in human cancer. We will generatecomprehensive synthetic lethal genetic interaction maps in yeast for the set of CIN genes altered inhuman cancer via DNA chip-based screens. RNAi will be used to validate phenotypes in mammaliancells.3). To establish a resource that systematically cross-references yeast and human CIN genes.Mammalian genes homologous to yeast genes under study will be identified via similarity to yeastprotein queries and stored in an annotated searchable database.4). To investigate the biological functions of NdclO and sumoylation at the kinetochore. Mutationsthat abrogate sumoylation of NdclO and other kinetochore proteins will be analyzed, and used asstarting points for genome-wide screensFurther elucidation of the genetic basis of CIN in yeast will provide a mechanistic basis forunderstanding this process in human cells, and will provide candidate genes for those CIN genesmutated in cancer. Therefore, knowledge gained from this work will provide insight into mechanismsof tumorigenesis.
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