Abstract: Series 114, Lecture 3

The Harvey Lectures Series 114 (2018—2019)

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Lecture #3: Thursday, January 17, 2019 — Time and Location

Our Ago-centric view of RNA interference

Leemor Joshua-Tor, PhD

Leemor Joshua-Tor, PhD

WM Keck Professor of Structural Biology

Howard Hughes Medical Institute, Cold Spring Harbor Laboratory

Cold Spring Harbor, New York

Dr Joshua-Tor's Website

We study the molecular basis of nucleic acid regulatory processes using the tools of structural biology and biochemistry. One such regulatory process is RNA interference (RNAi), in which a small double-stranded RNA triggers gene silencing. Our team offered critical insight when we solved the crystal structure of the Argonaute protein and identified it as the long-sought Slicer. We then went on to explore the mechanism of the slicing event. The structure of human Argonaute-2 (hAgo2) bound to a microRNA (miRNA) guide allowed us to understand the programmable nature of the system as well as the symbiotic relationship between Argonaute and the miRNA. In comparing the active hAgo2 with the inactive hAgo1 using structural and mutational analysis, we identified key parts of the protein that are required for slicing activity. The interaction between human Argonaute and GW182 is essential for downstream mRNA silencing by miRNAs. We showed that miRNA loading ehhances Ago’s affinity to GW182 and that GW182 can recruit up to three copies of Ago. This recruitment might account for the cooperativity that is observed when an mRNA is targeted by multiple miRNAs at adjacent sites. In addition to basic mechanisms of gene silencing, we have been studying the regulation of a particular miRNA, let-7, important in embryonic development and differentiation.