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New system cuts RNA using only small molecules

Researchers hijack natural enzymes to introduce click-chemistry fragments that trigger the breakdown of targeted RNA sequences

by Fernando Gomollón-Bel, special to C&EN
November 16, 2020

A team of researchers has developed a simple, selective system that uses only small molecules to cut certain RNA sequences to pieces (ACS Cent. Sci., 2020, DOI: 10.1021/acscentsci.0c01094). They can now study biochemical pathways by tracking which RNA sequences are broken down.

Scheme shows how an RNA methyltransferase can be repurposed to degrade RNA with the help of a degrading molecule.
Credit: ACS Cent. Sci.
Researchers hijack a methyl transferase enzyme using a modified cofactor that, instead of a methyl group, decorates the RNA strand with an alkyne fragment. Then, they use click chemistry to attach a degrader capable of breaking nucleosidic bonds.

“This is a tremendous breakthrough that will help us better map RNA modifications in cells,” says Kristin S. Koutmou, an expert in translational mRNA modifications from the University of Michigan who was not involved with the study. Established mapping techniques rely on expensive additional reagents such as enzymes and antibodies. They do not work in living cells. And the techniques are “sometimes less specific than you would think,” Koutmou says.

The new technique gives researchers the ability to degrade RNA by targeting natural modifications made to RNA in the cell, says Gonçalo J. L. Bernardes, of the University of Cambridge and the Institute of Molecular Medicine at the University of Lisbon, who co-led the study with Konstantinos Tzelepis, also of the University of Cambridge. Researchers who study RNA modifications sometimes use a system known as CRISPR-Cas13—a variation on the famous CRISPR-Cas9 system that targets RNA exclusively, but that requires genetic engineering. “Our system offers a solution to degrade RNA, like CRISPR-Cas13, albeit in a completely different fashion that uses only small molecules,” Bernardes says.

To achieve this, Bernardes and his colleagues hijacked a natural enzyme involved in RNA modification. In cells, methyl-transferase enzymes recognize certain RNA sequences, and then label them with methyl groups that regulate RNA activity. “We trick methyl-transferase enzymes into decorating RNA strands with alkyne moieties” instead, explains study author Sigitas Mikutis, by substituting their typical methyl-adding cofactor with a version that, instead, adds an alkyne fragment. Then, using a copper-catalyzed click reaction, they attach to the alkyne a degrader group that cuts the RNA strand at the site of methylation. “The degrader contains a terminal imidazole fragment capable of breaking nucleosidic bonds,” adds Mikutis. Subsequent analyses of the fragments allow researchers to map the methylation sites on the RNA sequences.

For David R. Liu, chemical biologist at Harvard University, this is a creative new tool for degrading RNA sequences in living cells. It could be easily be adapted to target different types of cellular RNA, he says. Bernardes says that the group plans to expand their methodology to other types of RNA modifications and eventually to DNA.



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