Molecular Mechanisms of Cell Cycle Dependent Gene Expression

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PROJECT SUMMARY Our research is focused on the mechanisms that control the cell cycle of growth and division. The identification of proteins and pathways that regulate the decision to divide has led to inhibitors to treat cancer. However, the shortcomings of these inhibitors make it clear that there are still many molecular aspects of cell-cycle control that we do not understand, and further research is needed to innovate improved therapies. The cell cycle consists of two waves of gene expression to replicate DNA and undergo mitosis. We will study the structure, function, and regulation of proteins that control this cell- cycle dependent gene expression. These proteins include the transcription factors or TFs (e.g. E2F, B- Myb, FoxM1) whose activity stimulates transcription, proteins that negatively regulate the TFs (e.g. Rb, CycF, and the MuvB complex), and the kinases (e.g. Cdk, Aurora A, and Plk1) that phosphorylate and modulate TF activity. We will use an integrated approach that combines structural biology with cell- based assays to determine how these proteins interact with each other and chromatin to control transcription. These studies will provide new mechanistic insights regarding how the cell cycle is controlled and how transcription factors directly modulate gene expression through influencing chromatin structure.