Understanding the mechanics of RNA interference (RNAi), a defense phenomenon that silences genes, might one day allow scientists to mimic this natural protective mechanism against viruses and create therapies for hard-to-treat diseases such as cancer, diabetes, and genetic disorders. In a study published in the online publication Proceedings of the National Academy of Science, Sanford-Burnham researchers reveal how SmD1—a messenger RNA (mRNA) processing protein—is a required component of RNAi.
“We have discovered that the mRNA splicing factor ‘SmD1′ is an indispensable part of the cell machinery that defends against viral infections. Without SmD1, RNAi silencing of destructive viral genes is defective,” said Rui Zhou, Ph.D., assistant professor in the Sanford Children’s Health Research Center.
RNAi works when a virus invades a cell and replicates, forming double-stranded RNA (dsRNA)—a form not normally found in nature—and triggers an enzyme called “Dicer,” to do exactly what you think it does—it dices up the dsRNA, essentially blocking a virus’s replication efforts.
For drug discovery, scientists are especially interested in what happens after dsRNA is chopped up. dsRNA fragments recruit the cell’s RNAi machinery to destroy mRNA—the molecular messages that carry the information coded in genes. The only mRNAs that are destroyed are those with sequences that correspond to the dsRNA triggers. By introducing dsRNA with sequences that correspond to genes that code for disease, scientists may be able to silence those genes to protect, restore, and maintain cell health.
Zhou led the study with a team of researchers that included Tariq M. Rana, Ph.D., professor in the Sanford Children’s Health Research Center and director of the RNA Biology Program at Sanford-Burnham; and Nobert Perrimon, Ph.D., professor in the Department of Genetics at Harvard Medical School. The study was performed in Drosophila—also known as a fruit fly—the most-widely used and genetically understood eukaryotic organism. Since all organisms use common genetic processes, understanding RNAi in these organisms helps us understand the process in humans.
“Prior to this study, we knew that SmD1 is an mRNA splicing factor in Drosophila and humans. Now, we know that in Drosophila, SmD1 interacts with Dicer, is required for antiviral defense and if absent, impairs the function of a cell’s RNAi machinery. Using this finding as a clue, we will now test whether SmD1’s dual role of mRNA splicing and RNAi is observed in humans as it is in Drosophila. Knowing whether SmD1 is required for RNAi in humans will contribute to our understanding of how the process can be used to advance the field of RNAi mediated therapeutics,” Zhou said.