Scientists identify hidden signals in RNAs that control protein synthesis

July 17, 2018

Scientists have long known that RNA codes instructions for making proteins. Building blocks that include RNA-, A, U, C, and Gs- form a model for the protein-producing machinery in cells. To make protein, the machinery locks the RNA at one end then sweeps along the RNA until it reaches an AUG chain, which is the signal to start translating the genetic code into a protein

. Protein-producing machinery frequently encounters sites that diverge from AUG of a building block (such as AUA). On the occasion, protein synthesis starts from these alternative starting sites. The way the protein-producing machinery chooses which alternative sites to use is a mystery.

In a new study published in Nature scientists describe how protein production mechanisms identify other sites of initiation. protein synthesis. "We discovered a mechanism that explains how sites are chosen for translation events that occur in traditionally untranslated regions and start at non-traditional start sites," says Eckhard Jankowsky, Ph.D. Center for Molecular Biology of RNA. at the Case Western Reserve University School of Medicine. "In recent years, it has become clear that translation in these areas is ubiquitous, but it is unclear how the starting sites are selected from the millions of possible sites."

In the new study, the Jankowsky team this is part of the protein-producing machinery, called Ded1p. Mutations in the human version of Ded1p are related to tumors and cognitive impairments. Viruses often target the critical enzyme to disrupt protein synthesis inside the cells. The Jankowsky team has created yeast cells with a defective Ded1p. The use of alternative starting sites for protein synthesis, such as AUA or AAG, has increased dramatically in these cells. However, the cells used only a small fraction of possible alternative sites.

The researchers found that the alternative starting sites chosen were next to regions where RNA folds on itself. Ded1p is an RNA helicase – an enzyme that unzips the folded RNA structures – but if it is defective, it is unable to do so. If they are folded, the RNA structures block the scanning by the protein-producing machinery and cause the synthesis of proteins from a nearby alternative start site. "Our results reveal a simple mechanism that involves the structure of RNA and a helicase." Jankowsky said. "If an alternative initiation site is close to the structure of RNA, it is used to start protein synthesis. Thus, the structure of RNA and the sites of initiation alternative are the signal to start protein production from non-traditional sites. " [Ded1p] all organisms, the results are probably universally applicable. Protein synthesis from translation initiation sites often impairs the production of key proteins encoded after AUG chains in RNA and thus determines the protein balance in the interior. cells. . "The human version of Ded1p, DDX3X, is implicated in many cancers and diseases," he says. Although further research is needed, the small molecules that help restore its function could theoretically repair the protein processes that have been broken up during the disease.