All cells must grow to a minimum size?the ?critical size??before they can commit to cell division. This size requirement prevents cells from becoming too big or too small, and it co- ordinates division with the availability of nutrients and cell growth in mass. As a consequence of size control, cells have narrow and characteristic distributions of cell size. Despite decades of study, it is unknown how cells measure and respond to size, or why mechanistically a minimum size is required for commitment to division. We have recently discovered that as G1 phase yeast cells grow in size, several hundred mRNAs are systematically expressed at higher and higher levels?they increase faster than the increase in size, and increase in concentration. Other mRNAs do the opposite?they increase slower than the increase in size, and so decrease in concentration. Strikingly, genes that activate the cell cycle fall into the first group, while genes that inhibit the cell cycle fall into the second group. This suggests that the ratio of activators to inhibitors increases as G1 phase cells grow, and that it is achievement of a critical ratio of many activators to inhibitors that triggers cell cycle entry. Here, we test the generality of this idea, by examining mRNA scaling-with-size in the yeast S. pombe and in human cells, and we will test two theories for the mechanism of differential-scaling-with-size. Finally we will ask if similar scaling occurs at the level of translation.
Other things being equal, one expects that when a cell grows in size, most of its components (mRNAs, proteins, lipids, carbohydrates, salts etc.) should increase in proportion to size. That is, their concentrations should remain constant. We have discovered a specific subset of mRNAs that fails to scale in proportion to size: some scale faster (increase in concentration), while others scale slower (decrease in concentration). Strikingly, activators of cell cycle scale faster, while inhibitors of cell cycle scale slower. This suggests that the growth-dependence of the cell cycle is caused by this differential scaling. We have two models supported by preliminary evidence of the mechanisms of this differential scaling, which we will test.