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A molecular machine’s secret weapon exposed

Illustration of RNA molecules in a cell
This illustration shows a mesh of RNA molecules inside a cell. It takes a lot of work to untie such complex knots. But one enzyme can bypass conventional methods. Using cryo-EM imaging, structural biochemists at Cold Spring Harbor Laboratory have discovered how Dis3L2 untangles and destroys unwanted RNAs. Image: © Christoph Burgstedt –
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RNAs are having a moment. The foundation of COVID-19 vaccines, they’ve made their way from biochemistry textbooks into popular magazines and everyday discussions. Entire companies have launched dedicated to RNA research. These tiny molecules are traditionally known for helping cells make proteins, but they can do much more. They come in many shapes and sizes, from short and simple hairpin loops to long and seemingly tangled arrangements. RNAs can help activate or deactivate genes, change the shape of chromosomes, and even destroy other RNA molecules.

Animated GIF of Dis3L2 changing shape
Here we see the molecular “machine” named Dis3L2 shape-shifting in order to unsheathe an RNA-splitting wedge. The dramatic transformation is unlike any other structural change previously observed in related enzymes.

Unfortunately, when RNA malfunctions, it can result in cancer and developmental disorders.

It takes a lot to keep RNAs in check. Our cells have molecular “machines” that eliminate RNAs at the right time and place. Most come equipped with a “motor” to generate the energy needed to untangle RNA molecules. But one machine in particular, named Dis3L2, is an exception. The enzyme can unwind and destroy RNA molecules on its own. This has puzzled scientists for years. Now, Cold Spring Harbor Laboratory (CSHL) biochemists have pieced together what’s happening.

It turns out Dis3L2 changes shape to unsheathe an RNA-splitting wedge.

Using state-of-the-art molecular imaging technology, CSHL Professor and HHMI Investigator Leemor Joshua-Tor and her team captured Dis3L2 at work. They fed the molecular machine hairpin snippets of RNA and imaged it getting “eaten” at various stages. After the machine had chewed up the tip of the RNA, it swung open a big arm of its body to peel apart the hairpin and finish the job. Joshua-Tor says of the discovery:

“It’s dramatic. We know things change conformation. They buckle. But opening something out like that and exposing a region in this way—we didn’t quite see something like this before.”

Photo of Meze in Joshua-Tor lab
Katarina Meze, the former graduate student in the Joshua-Tor lab who led this study, standing next to the lab’s cryo-EM imaging machine. The machine allows scientists to freeze molecules in place to study their structure and geometry.

Joshua-Tor’s team then began tinkering with the Dis3L2 machine, searching for the gears and parts enabling it to unwind and destroy RNA. The researchers narrowed it down to a protruding wedge left unsheathed after the machine shifted shapes. If the researchers removed the wedge, Dis3L2 could no longer untangle the RNA hairpin, putting the machine out of commission.

The findings reveal a surprising new way that RNA-controlling machines in our cells execute their tasks. Rather than solid structures, these molecular workhorses need to be considered malleable and versatile. This new outlook may help scientists develop better treatments for diseases and disorders caused by RNA gone haywire. “We have to start thinking about these things as much more dynamic entities,” Joshua-Tor says, “and take that into account when we are designing therapeutics.”

Written by: Luis Sandoval, Communications Specialist | | 516-367-6826


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National Institutes of Health, Cold Spring Harbor Laboratory School of Biological Sciences, Leslie C. Quick, Jr. Fellowship, Howard Hughes Medical Institute


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Meze, K., et al., “A shape-shifting nuclease unravels structured RNA”, Nature Structural & Molecular Biology, February 23, 2023. DOI: 10.1038/s41594-023-00923-x

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Principal Investigator

Leemor Joshua-Tor

Leemor Joshua-Tor

Professor, Director of Research & HHMI Investigator
W.M. Keck Professor of Structural Biology
Cancer Center Program Co-Leader
Ph.D., The Weizmann Institute of Science, 1991