Protein synthesis governs if, how fast, and how many times cells divide. Yet how protein synthesis is linked molecularly with cell division is unknown. We use budding yeast as a model system to answer this problem. Because yeast has unique properties, suited for genetic and biochemical experiments. New methodologies can identify transcripts that engage with the protein synthesis machinery, the ribosomes, in the process of translation. For the first time in the field, we applied this ribosome profiling methodology in synchronously dividing cells that maintained the physiological coupling of protein synthesis with their division. In this collaborative proposal, we will leverage these findings to tackle the long-standing problem of protein synthesis requirements for cell divisions.
In Aim 1, we will determine how translational control of lipogenic enzymes regulates the remodeling of cellular membranes during cell division. Furthermore, we will determine how protein synthesis adjusts the production of proteins that trigger duplication of the spindle pole body, an essential part of the machinery of chromosome segregation. We will also identify translationally regulated mRNAs under dietary restriction, which changes the size of cells and increases the number of times cells divide before they die.
In Aim 2, we will extend ribosome profiling to settings of specific ribosomal protein mutants that delay cell division and increase lifespan. These genetic interventions will enable us to identify mRNA targets of translational control that underpin cell division and replicative longevity when protein synthesis is limited. Knowing how translational control affects the timing and number of cell divisions will reveal fundamental links between cell growth, protein synthesis, cell division and aging, enabling novel therapeutic interventions in proliferative diseases.
This project is relevant to public health because identifying how protein synthesis affects cell division will expand our grasp of the control of cell proliferation and replicative longevity. Such processes play a key part in many diseases. Hence, the study we propose is relevant to NIH's mission because it will develop basic knowledge for progress in the treatment of disease.
