The overarching goal of this project is to understand how cell growth triggers cell division in yeast and in mammalian cells. Solving this question of has the potential to revolutionize our understanding of how cell division is regulated in both natural developmental contexts and in disease. Our work has fundamental implications for understanding how the most basic aspect of cell morphology, cell size, is controlled, and may identify novel molecular mechanisms that can rationally be targeted in cancer therapies. My laboratory recently made a breakthrough discovery in understanding how growth triggers division in budding yeast. While it was expected that growth would act to increase the activities of the cyclin-dependent kinases (Cdk) known to promote cell division, this is not the case. Rather, we found that cell growth acts in the opposite manner. Cell growth triggers division by diluting a protein that inhibits cell division, Whi5. This MIRA project aims to leverage our breakthrough discovery in understanding how growth triggers division in yeast to understand the underlying transcriptional mechanism in yeast and to understand how this works in mammalian cells. This is now possible thanks to the rapid advances in mammalian genome editing technologies that allow us to tag cell cycle regulators at their endogenous loci. We can now measure, for the first time, the dynamics of concentration changes of almost any protein expressed from its endogenous locus in individual growing and dividing cells. To determine the mechanisms linking growth to division, we will examine how cell size and growth impacts the concentration of key cell cycle regulators at single cell resolution. In addition, we aim to examine transcription as a function of cell size genomewide in both yeast and diverse human cell types to identify the underlying molecular mechanisms.
Cell size is an important cellular property that is controlled by tying division to growth. We aim to determine the molecular mechanism cells use to measure their size so that growth can trigger proliferation in both budding yeast and mammalian cells.