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Abstract: Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, surface transport, and, most importantly, biosynthesis. While some genes affecting cell size have been identified, the molecular mechanisms through which cell growth drives cell division had remained elusive. 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 proteins that inhibit cell division, Whi5 in yeast, and the retinoblastoma tumor suppressor Rb in human cells. Thus, inhibitor dilution provides one long sought mechanism coupling cell growth to cell division and it relies on the differential scaling of the biosynthesis of cell cycle activators and inhibitors molecules. How are some molecules synthesized to remain in proportion to cell size while others are synthesized in amounts that are independent of cell size? We have begun to elucidate the molecular mechanisms underlying size scaling across the proteome and have uncovered both transcriptional and post-transcriptional mechanisms that tune protein concentrations to enhance cellular function and control cell size.
Prof. Skotheim's interdisciplinary research group draws on diverse scientific cultures to develop a creative, rigorous and quantitative approach to the fundamental question of how growth drives cell division. His lab's diverse backgrounds include mathematics, physics, engineering, biochemistry, genetics, and cell, molecular, and systems biology, all reflecting his interdisciplinary training (BS Mathematics; BS Physics - MIT 1999; PhD Applied Mathematics - Cambridge 2004; Postdoctoral training Genetics, Cell, and Systems Biology - Rockefeller) The Skotheim Lab's prior and ongoing studies of the circuit responsible commitment to cell division will be invaluable for identifying small molecule inhibitors of cyclin D-Cdk4,6 substrate docking. First, his lab led an interdisciplinary effort to discover that Cyclin D docks the C-terminal helix of Rb to target it for phosphorylation by Cyclin D-Cdk4/6 complexes (Topacio et al 2019). Second, his lab has extensive experience with quantitative methods that are important for analyzing the effects of genetic or chemical perturbation to G1/S cell cycle control at single cell resolution. For example, using a live cell kinase activity reporter, they showed how there is an extremely sharp threshold for the restriction point, beyond which cells are committed to division despite the removal of growth factors (Schwarz et al 2018). These single cell analysis methods are highly sensitive and will be essential for analyzing how small molecules affect cell cycle progression. In addition, Prof. Skotheim has led several yeast studies identifying the underlying principles of G1/S regulation that have usefully served as hypothesis generators for how the human G1/S pathway works (Doncic et al., 2011, 2015).
Link to the Skotheim Lab: http://skotheimlab.com/