Cells need to accumulate enough precursors before they can divide, and it is thought that coordination between cellular metabolism and DNA replication determine when cells initiate their division. Yet, the mechanisms that link metabolic pathways with DNA replication in the nucleus of the cell remain largely unknown. Cells must also properly process and fold newly synthesized proteins. If new protein synthesis exceeds the capacity of the cell to correctly fold these proteins, a stress signaling pathway called the unfolded protein response (UPR), is triggered. Surprisingly, initiation of cell division is accelerated in yeast cells lacking a sensor signaling protein that triggers the UPR, suggesting that even in apparently unstressed cells the UPR delays initiation of cell division. This project will test the hypothesis that the UPR is a homeostatic mechanism uniquely positioned to gauge overall metabolic activity before DNA replication and, thereby, control cell division. Specifically, how the UPR controls known regulators of cell division, and how distinct metabolic parameters are coupled with the UPR and, thereby, affect initiation of cell division, will be examined. This research will impact the understanding of cell division mechanisms in a variety of fungal, plant, or animal systems, because the UPR is conserved in all eukaryotic organisms, from yeast to humans.
Broader impacts: While promoting basic scientific discovery, this project will provide the framework for the training and education of young scientists, both at the graduate and undergraduate level. These students will be involved in the production of scientific knowledge through experimentation and in its dissemination, by authoring manuscripts and presenting their work in scientific conferences. This is important for the subsequent career advancement of these students, especially since the majority of these researchers will likely be from under-represented minorities.
This project generated fundamental knowledge about genetic mechanisms that control initiation of cell division. Such processes play key roles in most diseases that arise from abnormal cell division. The same mechanisms also control biomass accumulation in biotechnological settings. With support from this project, we identified and reported in the primary scientific literature novel factors that control cell division. For example, we reported the first comprehensive dataset of all the genes in any organism required for the timely initiation of cell division. Our findings expanded by more than three times the number of genes known to affect the timing of initiation of cell division. We also developed novel approaches that allowed us to determine for the first time the size of cells when they are born, and how this property affects cell division. Our findings will certainly enable future studies to define how many pathways affect initiation of cell division, which factors operate within each pathway, and the extent of interactions between pathways. Taken together, the knowledge we generated should greatly facilitate efforts to program cell proliferation, for therapeutic or biotechnological applications. Finally, this project enhanced the research infrastructure of our institution, and it supported the training of more than twenty young scientists, at the graduate and undergraduate levels.
