Structural Studies Of Post-transcriptional Gene Regulati

Environmental Health Sciences

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Abstract

Post-transcriptional regulation of messenger RNA (mRNA) stability and translation are important control points for gene expression. The overall goal of this project is to generate and utilize structural information to enhance our understanding of these processes. We are conducting structural and biochemical studies of proteins that are involved in or affect the mechanism of RNA silencing. RNA silencing, the destruction of mRNA by double stranded RNA containing corresponding sequences, has proven to be a useful tool to knock out expression of target genes in eukaryotic cells and may have therapeutic potential. In the past few years, much has been learned about the mechanism by which RNA silencing occurs, including the identification of proteins involved in the process. We are studying the structure of a plant viral protein that suppresses RNAi by binding to the intermediate RNAs, small interferring RNAs (siRNAs), that direct mRNA destruction. We have determined the crystal structure of the p19 protein from Carnation Italian Ringspot Virus in complex with an siRNA. Biochemical studies have shown that p19 protein selects for an siRNA based on the length of the duplex region of the RNA. The presence of a 5' phosphate group is also important for recognition, but the 2 nt 3' overhanging ends are not important for recognition. Additional biochemical studies are ongoing to examine the ability of p19 protein to inhibit microRNA directed processes.