The Mechanism of Cell Size Regulation - Administrative Supplement

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PROJECT SUMMARY How cells regulate their size is an long-standing biological mystery. Proper size regulation is essential for cell viability. Dysregulation of cell size leads to cellular pathology and is associated with human disease, particular malignancies. Yet, little is know about the mechanisms of cell size regulation. We have recently made a important discovery regarding cell size regulation in fission yeast: two direct activators of mitosis, the Cdc13 cyclin and the Cdc25 phosphatase, are expressed in a size-dependent manner. This manner of expression is unusual because most proteins maintain a constant concentration as cells grow. However, this unusual behavior of two key cell cycle regulators supports the accumulating-activator hypothesis of cell size control. The accumulating-activator hypothesis posits that size- dependent accumulation of a limiting mitotic activator regulates cell size. The abundance of such an activator restrains mitosis when cells are small and express low amounts of the activator, but drives mitosis when cells are large and express high amounts of the activator. We will directly test the hypothesis that Cdc25 and Cdc13 are redundant accumulating activators in fission yeast. If they are, it will provide the first experimentally validated, mechanistic model for size control in any organism. Even if size control is more complicated than just the accumulation of Cdc25 and Cdc13, understanding the size-dependent accumulation of these two key cell cycle regulators will provide important insight into the open question of how proteins can be expressed in a size dependent manner. Therefore, we will dissect the regulation of expression of both Cdc25, which we have shown to be regulated transcriptionally, and Cdc13, which we have shown to be regulated post-transcriptionally.