The major focus of our laboratory is the molecular biology of eukaryotic chromosome transmission. Genetic and molecular approaches are used to study determinants that control the mitotic and meiotic segregation of chromosomes in the yeast Saccharomyces cerevisiae. Genetic perturbation causing a chromosome instability (CIN) phenotype in cancer cells is now widely recognized to be a major predisposing condition in cancer initiation and/or progression. S. cerevisiae has proven to be an excellent experimental organism for the study of mitotic cell division and the chromosome transmission cycle. One line of research is aimed at identifying genes that encode or regulate the function of kinetochore proteins that directly interact with centromeric DNA. A second line of research involves analysis of a large reference collection of mutants that are defective in chromosome segregation and that define genes required for kinetochore function, sister chromatid cohesion, chromosome structure, and control of cell cycle progression at mitosis. A third line of research focuses on the Anaphase Promoting Complex (APC), which acts as an E3 activity in the ubiquitination of key cell cycle regulatory proteins (eg., mitotic cyclins) that regulate transition from metaphase to anaphase and exit from mitosis. The results of our proposed research will provide a basic understanding of the mechanisms of chromosome transmission, and will therefore be directly relevant to an understanding of cancer mechanisms. The results may also be useful in developing strategies for cancer therapy and for sub-classification of tumors based on their CIN mutational spectrum.