Using new nuclear magnetic resonance (NMR) techniques previously developed to study protein transient states, scientists at the University of Michigan have visualized and analyze the fastest and smallest RNA switch to be discovered. These rare RNA micro-switches could provide new targets for drugs that treat a wide range of bacterial, viral, and genetic diseases.
2012 PECASE winner Daniel Larson and ENCODE researcher Piero Carninci will answer all your questions about their work.
“In the paper, we have unraveled the rules that govern RNA transient states, which is unprecedented for any system,” explained study author and University of Michigan professor of chemistry and biophysics Hashim Al-Hashimi. “To visualize transient forms for any system is already a major breakthrough, but to be able to describe the rules that govern their existence and be able to predict them, that’s a whole new level.”
RNA switches act as sensors within cells, alerting cellular machinery to respond to environmental changes such as shifts in pH or temperature. Previously, researchers have identified RNA macro-switches that monitor changes in shape and form, but those switches do not always respond quickly enough to these changes. But the RNA micro-switches identified in this new study provide cells with a much quicker response to environmental cues.
Because these brief transient states may appear only for a microsecond, scientists have had difficulty capturing them for study. “RNA exists in two forms: 99% of the form is, let’s call it the A-form; and 1% of the time it is this other form,” said Al-Hashimi. “So, being able to visualize that 1% is a challenge in physics and biophysics for something that is very small.”
To overcome this challenge, the team narrowed their search of potential RNA forms by computationally predicting these transient structures. Then, the group visualized the brief alternative states—also known as excited states—using a modified NMR spectroscopy approach. Finally, the team identified particular mutations that effectively trapped the transient RNA structures for observation.
Now, Al-Hashimi’s lab is analyzing the functional relevance of these switches to discover what they do in a biological context. Also, they are assessing them for their potential in drug discovery.
“It used to be thought, and still is the case now, that proteins do everything and that they are the drug targets. But roughly 95% of your DNA makes RNA, not proteins. This is seriously taking the whole approach to drug discovery and flipping it around,” explained Al-Hashimi.
1. Dethoff, E. A., K. Petzold, J. Chugh, A. Casiano-Negroni, and H. M. Al-Hashimi. 2012. Visualizing transient low-populated structures of RNA. Nature advance online publication(October).