Biosynthesis of proteins accounts for 30% or more of the nutrients and energy consumed by proliferating cells, and it is often dysregulated in human diseases such as cancer and neurological disorders. My research program aims to develop an experimentally-constrained, biophysical model for protein synthesis at the whole- cell level with the goal of predicting protein levels in normal and diseased cellular states. Our current focus is on deciphering the kinetics of ribosome motion on mRNAs and its effect on protein expression. This research builds on our recent discovery that synonymous codon usage is a potent determinant of ribosome kinetics and protein abundance during nutrient-limited growth of bacteria. Notably, our experimental observations are not explained by known hierarchies of codon usage bias or tRNA abundance. Our current results suggest that biased usage of specific codons can regulate protein expression across several domains of life from microbes to mammalian cells during fluctuations in nutrient availability. Our research strategy aims to establish the mechanism and gene targets for this previously unsuspected, synonymous codon dependent regulation of protein expression in bacteria and mammalian cells. Successful completion of this research will provide a molecular basis for understanding the consequences of several hundred synonymous mutations that have been recently implicated as drivers of cancer. In the longer term, the novel quantitative methods developed in our research program will provide a rigorous modeling framework for deriving experimentally- testable predictions from increasingly complex datasets such as ribosome occupancy measurements.
Public Health Relevance: Bacterial pathogens and cancer cells often face nutrient limitation in their natural environments. The proposed research will illuminate a mechanism of gene regulation during nutrient limitation that is based on the degenerate structure of the genetic code, and thus affects the expression of all proteins. Suppressing this mechanism using drugs might be a general and effective strategy to reduce the survival of bacterial pathogens and cancer cells in nutrient-poor environments.
| Darnell, Alicia M; Subramaniam, Arvind R; O'Shea, Erin K (2018) Translational Control through Differential Ribosome Pausing during Amino Acid Limitation in Mammalian Cells. Mol Cell 71:229-243.e11 |
| Ferrin, Michael A; Subramaniam, Arvind R (2017) Kinetic modeling predicts a stimulatory role for ribosome collisions at elongation stall sites in bacteria. Elife 6: |
