Unprecedented videos show RNA switching `on' and `off'
RNA strands invade, displace one another to enable genetic decision
making
Date:
March 28, 2022
Source:
Northwestern University
Summary:
Using new simulations, researchers discovered one part of
RNA smoothly invades and displaces another part of the same
RNA, enabling the structure to rapidly and dramatically change
shape. Called strand displacement, this mechanism appears to switch
genetic expression from 'on' to 'off'.
FULL STORY ========================================================================== Similar to a light switch, RNA switches (called riboswitches) determine
which genes turn "on" and "off." Although this may seem like a simple
process, the inner workings of these switches have confounded biologists
for decades.
==========================================================================
Now researchers led by Northwestern University and the University at
Albany discovered one part of RNA smoothly invades and displaces another
part of the same RNA, enabling the structure to rapidly and dramatically
change shape.
Called "strand displacement," this mechanism appears to switch genetic expression from "on" to "off." Using a simulation they launched last
year, the researchers made this discovery by watching a slow-motion
simulation of a riboswitch up close and in action.
Affectionately called R2D2 (short for "reconstructing RNA dynamics from
data"), the new simulation models RNA in three dimensions as it binds to
a compound, communicates along its length and folds to turn a gene "on"
or "off." The findings could have potential implications for engineering
new RNA-based diagnostics and for designing successful drugs to target
RNA to treat illness and disease.
The research is described in a new paper published today (March 28)
in the journalNucleic Acids Research (NAR), which has designated the
study as a "Breakthrough Article." NAR reserves "Breakthrough Article"
status for the most high-impact studies answering long-standing questions
in nucleic acids research.
"We have found this strand displacement mechanism occurring in other
types of RNA molecules, indicating this might be a potential generality
of RNA folding," said Northwestern's Julius B. Lucks, who co-led the
study. "We are starting to find similarities among different types
of RNA molecules, which could eventually lead to RNA design rules for
folding and function." Lucks is a professor of chemical and biological engineering in Northwestern's McCormick School of Engineering and a
member of the Center for Synthetic Biology and of the Chemistry of Life Processes Institute. He co-led the study with Alan Chen, an associate
professor of chemistry at the University at Albany in New York.
========================================================================== R2D2's 'groundbreaking approach' Although RNA folding takes place in
the human body more than 10 quadrillion times per second -- every time
a gene is expressed in a cell -- researchers know very little about the process. To help visualize and understand the mysterious yet crucial
process, Lucks and Chen unveiled R2D2 last year, in a paper published
in the journal Molecular Cell.
Employing a technology platform developed in Lucks' lab, R2D2 captures
data related to RNA folding as the RNA is being made. Then, it uses computational tools to mine and organize the data, revealing points
where the RNA folds and what happens after it folds. Angela Yu, a former student of Lucks, inputted this data into computer models to generate
accurate videos of the folding process.
"What's so groundbreaking about the R2D2 approach...is that it combines experimental data on RNA folding at the nucleotide level with predictive algorithms at the atomic level to simulate RNA folding in ultra-slow
motion," said Dr. Francis Collins, director of the National Institutes of Health, in his February 2021 blog. "While other computer simulations have
been available for decades, they have lacked much-needed experimental data
of this complex folding process to confirm their mathematical modeling." Long-distance communication While Lucks and Chen's previous simulations visualized the folding of an ancient RNA called SRP, the new movies model
a riboswitch from Bacillus subtilis, a common bacterium found in soil.
========================================================================== Riboswitches have two basic parts. One part binds to a compound. Then, depending on how the compound is bound, the second part causes the RNA
to fold into a shape that allows it to control gene expression. While
these two parts are intertwined and overlapping in many riboswitches,
the Bacillus subtilis is different.
"What's strange is that they are separated by a long distance, but the
bound molecule can cause large functional changes," Lucks said. "If the chemical binds at one end, then how is that communicated downstream to
the other end of the RNA? It's been a mystery." Lucks, Chen and their
teams found the riboswitch likely communicates downstream through the
strand displacement mechanism. In response to the chemical binding,
the strand exchange process triggers structural switching between "on"
and "off" states.
Optimizing RNA for drugs and diagnostics With this new understanding,
Lucks believes the stage is set for optimizing the riboswitch to perform
useful tasks. The switch could be used for synthetic biology-based
diagnostics, for example -- engineered to turn "on" in the presence of
an environmental contaminant. By studying this riboswitch, researchers
also will learn lessons that could lead to new approaches to create RNA-targeted drugs or new classes of antibiotics.
"Many diseases are likely caused by something going awry at the RNA
level," Lucks said. "The more we know about this, the better we can design
RNA targeting drugs and RNA therapeutics." The study, "Cotranscriptional
RNA strand exchange underlies the gene regulation mechanism in a
purine-sensing transcriptional riboswitch," was supported by National
Institute of General Medical Sciences (award numbers 5T32GM008382, R35GM13346901 and 1R01GM130901) and the National Science Foundation
(award number PHY1914596).
========================================================================== Story Source: Materials provided by Northwestern_University. Original
written by Amanda Morris. Note: Content may be edited for style and
length.
========================================================================== Related Multimedia:
* YouTube_video:_RNA_switches_'on'_and_'off' ========================================================================== Journal References:
1. Luyi Cheng, Elise N White, Naomi L Brandt, Angela M Yu, Alan A Chen,
Julius B Lucks. Cotranscriptional RNA strand exchange underlies
the gene regulation mechanism in a purine-sensing transcriptional
riboswitch.
Nucleic Acids Research, March 28, 2022; DOI: 10.1093/nar/gkac102
2. Angela M Yu, Paul M. Gasper, Luyi Cheng, Lien B. Lai, Simi Kaur,
Venkat
Gopalan, Alan A. Chen, Julius B. Lucks. Computationally
reconstructing cotranscriptional RNA folding from experimental data
reveals rearrangement of non-native folding intermediates. Molecular
Cell, 2021; 81 (4): 870 DOI: 10.1016/j.molcel.2020.12.017 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220328133656.htm
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