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A new study led by Northwestern University is unraveling the mystery of how RNA molecules fold up to fit inside cells and perform specific functions. The findings could potentially break down a barrier to understanding and developing treatments for RNA-related diseases, including spinal muscular atrophy and possibly even the novel coronavirus.
“RNA folding is a dynamic process fundamental to life,” said Julius B. Lucks of Northwestern, who led the study. “RNA is a really important part of diagnostic and therapeutic design. The more we know about the folding and complexity of RNA, the better we can design treatments.”
Using data from RNA folding experiments, the researchers generated the very first films based on data on how RNA folds when it is made by cellular machinery. Watching their videos of this folding happening, the researchers found that RNA often folds in surprising, perhaps unintuitive, ways, such as knotting itself – then immediately unbinding to reach its final structure.
“Folding takes place in your body over 10 quadrillion times per second,” Lucks said. “It happens every time a gene is expressed in a cell, but we know so little about it. Our films finally allow us to see the folding happen for the first time.”
The research will be published on January 15 in the journal Molecular cell.
Lucks is an associate professor of chemical and biological engineering at the McCormick School of Engineering at Northwestern and a member of the Center for Synthetic Biology at Northwestern. He co-directed the work with Alan Chen, associate professor of chemistry at the University of Albany.
Although RNA folding videos exist, the computer models that generate them are full of approximations and assumptions. Lucks’ team has developed a technology platform that captures data on RNA folding during RNA manufacturing. His group then uses computational tools to extract and organize the data, revealing the points where RNA folds up and what happens after it folds. Lucks alumnus Angela Yu entered this data into computer models to generate accurate videos of the bending process.
“The information we provide to algorithms helps computer models correct themselves,” Lucks said. “The model performs precise simulations that are consistent with the data.”
Lucks and his colleagues used this strategy to model the folding of an RNA called SRP, an ancient RNA found in all realms of life. The molecule is well known for its hairpin shape. Watching the videos, the researchers discovered that the molecule knots and unravels very quickly. Then it suddenly switches into the correct hairpin structure using an elegant bending path called plug-mediated strand displacement.
“To our knowledge, this has never been seen in the wild,” Lucks said. “We believe RNA has evolved to untie knots because if knots persist it can render RNA non-functional. The structure is so essential to life that it has had to evolve to find a way out of it. ‘a knot.”
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The study “Computer-based reconstruction of co-transcriptional RNA folding pathways from experimental data reveals rearrangement of non-native folding intermediates” was supported by the National Institutes of Health (price numbers T32GM083937, 1DP2GM110838 and GM120582), the National Science Foundation (award numbers MCB1651877 and 1914567) and the Searle funds of the Chicago Community Trust.
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