Regulation of Protein Synthesis by Synonymous Codon Usage

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PROJECT SUMMARY Translation of mRNAs by ribosomes is an essential process in all living cells, and it is frequently dysregulated in many cancers and neurodegenerative diseases. The initiation stage of translation is usually thought of as the major point for regulation of protein expression and mRNA stability. However, we and others have recently char- acterized a critical and multi-faceted role for the elongation stage of translation in regulation of gene expression. During our last funding period, we identiߑed a novel role for synonymous codon usage in regulating elongation rate and protein expression from mammalian mRNAs during amino acid limitation. Our studies of synonymous codon effects led to the major discovery that collisions between multiple ribosomes serve as a signal for cells to recog- nize and rescue stalled ribosomes. Furthermore, we observed that high initiation rates counter-intuitively decrease protein expression and stability of mRNAs undergoing ribosome collisions. Emerging from these advances is a role for the mRNA as a dynamic platform for multi-factorial interactions between large macromolecular complexes during translation. In the next project period, we will dissect such interactions that occur between elongating ri- bosomes, initiating ribosomes, and mRNA decay factors. The goal of these studies will be to comprehensively deߑne the set of ribosome-mediated interactions that are important for accurate prediction of gene expression in the speciߑc contexts of mRNA turnover, short upstream open reading frames, and ribosomopathies. Towards this goal, we will leverage our unique interdisciplinary approach combining quantitative high throughput experiments with computational kinetic models. Successful completion of our research will provide a mechanistic framework to predict the cellular consequences of disease-associated mutations in ribosomes and mRNA decay factors, as well as in noncoding and synonymous sites of speciߑc mRNAs.