A remarkable feature of cells is their ability to divide accurately even when environmental or intracellular conditions show strong variation. Thus, cells and organisms exhibit an intrinsic `robustness' that buffers against fluctuations while allowing high-fidelity cell division, which is vital for genome maintenance and human health. The molecular toolkit necessary for cell division has been studied in great detail in yeast and humans, however, we do not know how the component parts work together to establish robustness. To understand the underlying mechanisms, it is necessary to explore how single cells respond to controlled perturbations and to combine this information with a theoretical framework of the underlying regulatory circuits. This project will globally examine the extent and limits of cell division robustness in fission yeast and determine which underlying molecular features allow robustness. Specifically, we will precisely titrate intracellular protein concentrations or modify extracellular conditions and analyze cell division accuracy by quantitative single cell imaging. To develop hypotheses on the mechanisms that establish robustness, these results will be combined with computational models of the underlying circuits. Model simulations can suggest important network features that allow robustness, which will then be tested in specific experiments. The successful completion of this work will create a first map of robustness in a eukaryote, which systematically describes when cell division robustness breaks down and pinpoints the critical network properties at the ?fragile edges? of cell division. Besides understanding a fundamental biological problem, our study can be a stepping stone for work in human cells, where personalized cancer therapy will benefit from knowledge on the mechanisms that underlie the robustness and fragility of cell division.
/ Relevance to Public Health Cell division is necessary for life, but uncontrolled cell division can threaten life, as is the case in cancer. This work will identify characteristics of cell division that may help to identify more specific therapeutic approaches that limit uncontrolled division.
|Gross, Fridolin; Bonaiuti, Paolo; Hauf, Silke et al. (2018) Implications of alternative routes to APC/C inhibition by the mitotic checkpoint complex. PLoS Comput Biol 14:e1006449|