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Dr. Nils G. Walter

University of Michigan-Department of Chemistry

September 20, 2019 – Fall Seminar

Time and Location: 12 Noon in Meyerhoff Chemistry Building, Room 120

Host: Dr. Minjoung Kyoung

The RNA nanomachines of gene expression dissected at the single molecule level

Over two decades, the Walter lab has contributed to the RNA field by building a broad research portfolio focused on dissecting the mechanisms of the nanoscale RNA machines of gene expression – ranging from small viroidal ribozymes and bacterial riboswitches to the eukaryotic spliceosome – by single molecule fluorescence microscopy.  Leveraging this expertise, the two long-term goals of our current work are to: 1.) Apply our established mechanistic enzymology approaches to an ever broader set of RNAs involved in regulating transcription, translation and splicing, seizing the opportunities arising from the continuing discoveries of new functional RNAs.  2.) Push the limits of our approaches to be able to probe increasingly complex biological contexts and mechanisms since unexpected discoveries – as we found – often await where individual RNA nanomachines interact.  In pursuit of these goals, we will address the overarching hypothesis that dynamic RNA structures are a major determinant of the outcomes of gene expression, often in ways that have been overlooked by a field that historically was rooted in genetics, where genes regularly were drawn as rectangular boxes, and function commonly was thought of as dictated by sequence rather than structure.  Encapsulating the power of our pursuit, we recently combined single-molecule, biochemical and computational simulation approaches to show that transcriptional pausing at a site immediately downstream of a riboswitch requires a ligand-free pseudoknot in the nascent RNA, a precisely spaced consensus pause sequence, and electrostatic and steric interactions with the exit channel of bacterial RNA polymerase.  We posit that many more examples of such intimate structural and kinetic coupling between RNA folding and gene expression remain to be discovered, leading to the exquisite regulatory control and kinetic proofreading enabling all life processes.  Thinking ahead, we are also developing tools to observe single RNA nanomachines in action within their natural habitat, inside living cells.