FUNCTIONAL DETERMINANTS OF CHROMOSOME SEGREGATION IN YEAST

Johns Hopkins University, Baltimore MD

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Abstract

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