RNA-Splitting Wedge Secret to Dis3L2’s Controlling Capabilities

Researchers at Cold Spring Harbor Laboratory have determined how the enzyme Dis3L2 is able to unwind RNA molecules as well as destroy them, which is a unique capability among the molecular machines that keep RNAs in check. According to their study, published in Nature Structural and Molecular Biology, Dis3L2 is malleable and versatile and changes its shape to unsheathe an RNA-splitting wedge.

Using state-of-the-art molecular imaging technology, CSHL Professor 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. 

“It’s dramatic," Joshua-Tor says. “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.”

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.”