Convergent studies over the past few years have revealed a universal mechanism for coordinating the cell cycle in eukaryotic cells. Checkpoint controls monitor the progress of key cell cycle events, and act to delay cell cycle progression if these events have not been completed, ensuring that critical events of the cell cycle occur in the proper order. Cells in which any form of checkpoint control is inoperative can no longer ensure the accurate transmission of chromosomes to daughter cells, and therefore display a greater degree of genome instability. Such genome instability is a common characteristic of cancer cells, and allows development of malignancy within an accelerated timeframe. Thus, understanding how checkpoint controls work is a priority for cancer research. Preliminary results are presented demonstrating the existence of a novel type of checkpoint control that responds to defects in cell polarity in budding yeast. This checkpoint delays entry into mitosis in cells that have not formed a bud. The delay is predominantly mediated by inhibitory tyrosine phosphorylation of the master cell cycle regulatory protein kinase Cdc28. The long-term goal of this application is to elucidate the molecular basis of this morphogenesis checkpoint pathway. The end point of the pathway will be addressed by a biochemical analysis of checkpoint regulation of Swe1 (the sole known kinase that phosphorylates Cdc28 on tyrosine), and a genetic analysis to identify other upstream regulators of Cdc28 tyrosine phosphorylation. The source of the checkpoint signal will be examined by determining whether the defects in a variety of known morphogenesis mutants trigger the checkpoint pathway. Comparison of mutants that do or do not trigger the pathway should be very informative as to the structure monitored by the checkpoint. Finally, a genetic strategy is proposed for the isolation of genes that are required for the operation of the checkpoint pathway. Genetic, molecular, and biochemical characterization of these genes should yield insights into how the checkpoint transmits information about the shape of the cell to the cell cycle regulators that phosphorylate Cdc28.
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