Monday, 27 January 2014 00:00

Bioinformatics Unwinds Twister, a New Class of RNA-Enzyme

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twisterThe lower left hieroglyph shows the “twisted flax”
symbol for which the twister ribozyme was named
by researchers at Yale.
In the "big data" realms of genome sequencing, there are many surprises left to be untangled. A new bioinformatics paper published January 10 in Nature Chemical Biology unwinds one—a new class of RNA-catalysts.1

Until relatively recently, the only known biological catalysts were proteins, specifically enzymes. But back in 1967, Francis Crick, Carl Woese, and Leslie Orgel proposed that RNA could also act as a catalyst. However, it wasn't until the 1980s that an RNA-enzyme, or ribozyme was discovered by Thomas Cech and Sidney Altman, winning them the 1989 Nobel Prize in Chemistry. Still only 10 classes of ribozymes have been discovered since the 1980s.

Now Adam Roth, Ronald Breaker, and colleagues at Yale University have identified a new ribozyme class. They used a unique bioinformatic approach  to look for new riboswitches. "Riboswitches are structured RNAs that are very conserved in sequence and structure... they control gene expression in response to metabolites in bacterium," according to Roth who is a postdoctoral fellow in the Breaker lab. The researchers were mining genome sequences for conserved RNA structures to find these riboswitches when they stumbled on this new class of ribozymes.

They named this class of looped ribozyme structures, made up of fewer than 50 nucelotides, "twister," not for Hasbro's colored-circle contortionist game but for the ancient Egyptian hieroglyph that represents "twisted flax." Roth recalled that Breaker suggested that the lab look at hieroglyph charts for something that resembled the ribozyme's secondary structure. "The twisted flax hieroglyph looks exactly like the consensus secondary sequence model of the ribozyme. It was perfect," Roth said.

Nearly 2,700 ribozymes fit into the new twister class structure, and twister ribozymes were found in many species of bacteria and eukarya like worms, plants, fish, and wasps, says Roth. "I think one of the reasons ribozymes and riboswitches were only discovered relatively recently, even though bacteria are chock full of them, is because they weren't appreciated. There's a bias against nucleic acids because the prevailing view is that all the tough [cellular] jobs are done by proteins." New bioinformatics approaches are changing that, said Roth. "New search methods deploy more sophisticated algorithms and the databases are growing," he explained, which leads researchers to find new things such as RNA-enzymes.

The new twister class appears to function in a similar genetic context as that of the hammerhead ribozymes, suggesting that the two classes might function interchangeably. Indeed, like the hammerheads, the twisters discovered by Roth and colleagues are self-cleaving in vitro and self-catalytic in vivo. "All of the examples we tested in test tubes underwent robust self-cleavage. That means it must be involved in RNA processing." But a big mystery remains for all self-cleaving ribozymes, said Roth, "What are their biological functions?"

1Roth A, Weinberg Z, Chen AG, Kim PB, Ames TD, & Breaker RR (2014). A widespread self-cleaving ribozyme class is revealed by bioinformatics. Nature chemical biology, 10 (1), 56-60 PMID: 24240507

Christina Szalinski

Christina is a science writer for the American Society for Cell Biology. She earned her Ph.D. in Cell Biology and Molecular Physiology at the University of Pittsburgh.

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