A new study led by Northwestern University reveals the mystery of how RNA molecules fold to adapt to cells and perform specific functions. The results could break down a barrier to understanding and developing treatments for RNA-related diseases, including spinal muscular atrophy and perhaps even the new coronavirus.
“RNA folding is a dynamic process that is critical to life,” said Julius B. Lucks of Northwestern, who led the study. “RNA is a really important piece in 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 first films based on data on how RNA folds as it is made with cellular machinery. Seeing how their videos of this folding came about, the researchers found that RNA often folds in surprising, perhaps unintuitive, ways, such as tying itself into knots and untying it immediately to reach its structure. final.
“Folding takes place in the body more than ten trillion 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 allow us to see the folding for the first time.”
The research will be published in the journal on January 15 Molecular cell.
Lucks is an associate professor of chemical and biological engineering at Northwestern McCormick School of Engineering and a member of the Northwestern Center for Synthetic Biology. He co-directed the work with Alan Chen, an associate professor of chemistry at Albany University.
Although RNA folding videos exist, the computer models that generate them are full of approximations and assumptions. The Lucks team has developed a technology platform that captures data on RNA folding as it is being manufactured. His group then uses computational tools to extract and organize the data, revealing points where RNA folds and what happens after it folds. Angela Yu, a former student of Lucks, introduced this data into computer models to generate accurate videos of the folding process.
“The information we provide to algorithms helps computer models correct themselves,” Lucks said. “The model makes accurate simulations that are consistent with the data.”
Lucks and his collaborators used this strategy to model the folding of an RNA called SRP, an ancient RNA that is found in all realms of life. The molecule is well known for its unique needle shape. Upon watching the videos, the researchers discovered that the molecule binds to a knot and detaches very quickly. Then, it is suddenly thrown towards the correct structure, similar to a fork, by means of an elegant folding path called displacement of the chain mediated by the tip.
“To our knowledge, this has never been seen in nature,” Lucks said. “We believe that RNA has evolved to detach from the knots because if the knots persist, it can make the RNA not work. The structure is so essential to life that it had to evolve to find its way. get out of a knot “.
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The study “Computational reconstruction of cotranscriptional RNA folding pathways from experimental data reveals the rearrangement of non-native folding intermediates,” received support from the National Institutes of Health (prize numbers T32GM083937, 1DP2GM110838, and GM120582) , the National Science Foundation (awards MCB1651877 and 1914567) and the Searle funds of the Chicago Community Trust.
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