We had previously shown that S. cerevisiae SPT4 contributes to the proper localization of evolutionarily conserved centromeric histone H3 variant (CenH3) Cse4p. The major research goal of our laboratory is to investigate the molecular mechanisms that regulate the function of Cse4p and its interacting partners (Scm3p and Histone H4) to mediate faithful chromosome segregation. We investigated the mechanism of Cse4p localization and have established that mislocalization of Cse4p and altered histone stoichiometry lead to defects in chromosome transmission. Our studies have also shown that overexpression Scm3p and its human homolog HJURP leads to genome instability in yeast and human systems. We examined the effect of chromatin modifiers and post-translational modification of kinetochore proteins on the assembly/function of CenH3 chromatin. Our results showed that hypoacetylation state of centromeric histone H4 is critical for faithful chromosome segregation. Our recent results with Cse4p localization and histone dosage in S. cerevisiae are consistent with those in S. pombe, suggesting conservation of the underlying mechanisms. We have also done genome wide screens using heterozygous dipolid strain collection of about 6000 strains of budding yeast to define genes that are haploinsufficient for chromosome stability. Results from these analyses has allowed us to define evolutionarily conserved pathways that maintain genome stability in yeast and humans. Our research on the molecular determinants of faithful chromosome transmission in S. cerevisiae will help us understand analogous processes in humans and their implications in human disease. Our laboratory is uniquely poised to utilize conventional genetic, biochemical, and cell biology approaches, as well as high-throughput genomic analysis for our research projects. We use an array of gene-deletion strains and a colony-picking robot for the identification of possible cancer drug targets and also for genetic screens by synthetic genome analysis (SGA), developed in the laboratory of Charlie Boone (University of Toronto).
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