The most stunning development of the last decade in the field of RNA biology and biochemistry was the discovery of phenomena collectively described as RNA interference (RNAi). These mechanisms regulate gene expression through the actions of microRNAs (miRNAs), a family of evolutionarily conserved and endogenously expressed non-coding RNAs. Important aspects of mature miRNA biosynthesis remain poorly understood; this CAREER project will address several fundamental questions using an alliance of NMR structural and biochemical investigations to fill major gaps in our knowledge of the intriguing miRNA world. The long-term objective of this project is to understand the principles of miRNA processing at the molecular level, in particular the fundamentals of early primary (pri-)miRNA recognition by the microprocessor complex. Ultimately, the goal is to test the overall hypothesis that so far unknown miRNA structural characteristics exist that define the underlying determinants of microprocessor substrate specificity.
Broader Impacts: Knowledge of the structure of miRNAs and their complexes with cellular factors involved in processing is central to understanding gene regulation. Unraveling specific structural features of pri-miRNAs would allow for a more accurate prediction of bona fide miRNA precursor sequences. In turn, a comprehensive understanding of miRNA biosynthesis and function would facilitate optimization of gene inactivation strategies mediated by artificial, small interfering (si)RNAs. This CAREER project describes research at the interface of structural biology, biochemistry, and genetics and provides ample opportunities for collaborative research exposing undergraduate and graduate students as well as postdoctoral fellows to the interdisciplinary nature of modern research. The main educational goal is to establish a comprehensive NMR based Structural and Functional Biology (NMR-SFB) training program that exposes students to ongoing, cutting-edge research, integrated within the Center for Structural Biology at MUSC. A key outreach effort, the 1st NMR Summer Camp, was established in May 2008. The Summer Camp will be repeated annually; the long-term goal is to attract and develop the next generation of scientists with a passion for cutting-edge NMR and Structural Biology in South Carolina, with special emphasis on SC's four-year colleges and minority-serving institutions.
