CAREER: Molecular level consequences of mRNA modification

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Cells face the daunting challenge of accurately synthesizing the correct number of proteins at the right time. Messenger ribonucleic acids (mRNAs) serve as blueprints for protein synthesis, and chemical modification of mRNA presents one avenue for cells to regulate protein production. Despite a rapidly growing recognition of their importance, fundamental questions regarding the identity, prevalence and functional consequences of mRNA modifications remain to be answered. This project will fill critical knowledge gaps to enable a molecular level understanding of how mRNA modifications impact protein synthesis. Such a framework will be imperative for ascertaining the contributions of mRNA modifications to key biological processes. This research provides training opportunities for students and is combined with a concurrent education plan aimed at increasing biochemical literacy in the public and motivating a future generation of scientists. Efforts include the development and presentation of hands-on educational experiences through the University of Michigan Museum of Natural History (UMMNH).Pioneering studies of mRNA modifications mapped the locations of individual chemical modifications to thousands of RNA molecules. However, it remains unclear how (or, in many cases, if) most modifications fundamentally change the functional properties of mRNAs to alter the expression and/or identity of the resulting proteins. This project uses a comprehensive set of biophysical chemistry and cell-based experiments to develop a mechanistic foundation for understanding the influence of chemical modifications on how the ribosome ‘reads’ the mRNA code. Furthermore, mass- spectrometry tools will be developed and implemented to ascertain the identity of modifications in yeast mRNAs and the MS2 bacteriophage RNA genome. The integrated application of direct and quantitative approaches to study the functional impact of mRNA modifications on translation is a distinguishing feature of this project. Together, these studies will reveal the molecular-level consequences of mRNA modifications on protein synthesis.This project is jointly funded by the Genetic Mechanisms program of the Molecular and Cellular Biosciences Division in the Biological Sciences Directorate and the Chemistry of Life Processes program of the Chemistry Division in the Mathematical and Physical Sciences Directorate.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.