Identifying and functionally characterizing the molecular determinants of chromosome stability in higher eukaryotes

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A stable genome is a fundamental property of all eukaryotes that is essential for the maintenance and accurate partitioning of DNA into daughter cells. Thus, genome stability is critical for normal cell function, physiology and species survival. Chromosome stability (CS), or the accurate maintenance of normal chromosome numbers and DNA content, is vital for genome stability, yet a huge gap exists in our fundamental understanding of the genes, proteins and cellular processes (i.e. molecular determinants) that regulate CS. My NSERC Discovery Program (DP) will fill this gap by identifying and functionally characterizing the molecular determinants of CS, to provide unprecedented insight into genome stability and normal cell function.******My DP has developed novel, quantitative imaging tools to identify and functionally evaluate CS genes and proteins. Bolstered by an industrial partnership that enhances my analytical capabilities and throughput, I am now applying these innovative tools to gain unparalleled insight into the molecular determinants of CS in higher eukaryotes. My initial focus stems from my unpublished pilot work that identified three members of the Condensin Complex as potential CS genes. In humans, there are two Condensin complexes (8 total proteins) that function to compact DNA into chromosomes, particularly during mitosis. Data from others suggest that aberrant chromosome compaction adversely impacts mitotic fidelity and leads to the loss of CS; however, the link between Condensin and CS has not been fully elucidated. Using genetic, biochemical and cell biology methods, I will gain a detailed understanding of the fundamental roles each Condensin protein has in CS. To gain further insight into the molecular determinants of CS, I will screen 501 candidate CS genes identified through cross-species approaches. I will quantitatively assess each gene as above, and generate a prioritized list from which I will functionally evaluate the top 10 candidates to determine their fundamental roles in CS. ******Collectively, my DP will yield important new knowledge that will advance our fundamental understanding of CS and its impact on genome stability and normal cell function in higher eukaryotes. More specifically, my DP will define the roles each Condensin protein has in CS, and will identify and functionally characterize novel genes and proteins to determine their essential roles in CS. Accordingly, my DP will impact and be of interest to geneticists and cell biologists, but will also generate applied and translational interest as well.******Trainees will benefit from my highly productive and collaborative research program. Trainees will receive comprehensive technical, conceptual and theoretical training in genetics, molecular/cell biology and CS to advance their specific projects, which will also strategically position them for related training and job prospects within academia and industry.