Sugar isn’t just for sweets. Inside cells, sugars attached to proteins and fats help molecules recognize one another—and let cells communicate. Now, for the first time, researchers report that sugars also appear to bind to some RNA molecules, the cellular workhorses that do everything from translating DNA into proteins to catalyzing chemical reactions. It’s unclear just what these sugar-coated RNAs do. But if the result holds up, it suggests vast new roles for RNA.
The report, posted to the preprint server bioRxiv on Monday, drew immediate Twitter responses verging on the hyperbolic: “a new era is starting!!” wrote one scientist. “A brilliant example of how collaboration … can alter the face of biochemistry as we know it!” wrote another. “This is a mind-blowing result,” tweeted a third. Asked by Science for comment, scientists were somewhat more measured. “This is a profound observation that nobody anticipated,” says Mark Lehrman, a pharmacologist at the University of Texas (UT) Southwestern Medical Center in Dallas who was not involved in the work. That profound observation still spurs caution: Others aren’t yet convinced about the basic findings.
The notion that RNAs might be modified by other molecules isn’t new. Chuan He, an RNA chemist at the University of Chicago in Illinois, notes that researchers have observed some 170 different chemical modifications to RNA—a methyl group here or an acetyl group there—that, among other functions, make sure RNA winds up in one cellular compartment or another. But until now, no one had seen complex sugars modify RNAs.
In the bioRxiv preprint, researchers led by glycochemist Carolyn Bertozzi and postdoc Ryan Flynn of Stanford University in Palo Alto, California, used a wide array of chemical analyses to examine RNA deep within the cell lines of mice, hamsters, and humans. They found that sugar groups called N-linked glycans bind to a subset of RNAs through one of their chemical letters called guanosine. Those most likely to be sugary, Bertozzi and her colleagues found, are small RNAs known as Y RNAs, which don’t code for proteins, but appear to play a part in DNA replication. The researchers even observed the sugary RNAs in cells isolated from living mice.
“I’m pretty convinced by those data that they are seeing RNA modifications,” says Laura Kiessling, a glycochemist at the Massachusetts Institute of Technology in Cambridge. However, she notes that many questions remain: “Exactly what is modified and how is still a big mystery.”
Bertozzi and her colleagues suggest the RNA could acquire its sugars from the same enzymes that cells use to add sugars to proteins. One such enzyme is OST, which functions by first cutting N-linked glycans off lipids and then adding them to proteins. Bertozzi and her colleagues found that RNAs were modified exclusively by N-linked glycans. And when they blocked the action of OST, RNA-sugar complexes failed to show up, suggesting OST may be transferring sugars to RNA.
But OST comes in two forms. And one of those simply cuts glycans off lipids without transferring them, making it possible that those free-floating sugars simply react with RNAs floating nearby. If an enzyme-controlled reaction attaches glycans to RNAs, that would suggest the cell is spending energy to carry out a specific function, Kiessling says. But if it’s just a side reaction, “that would be less interesting,” she adds.
Another concern says a scientist who asked not to be identified, is that the RNAs may not be modified at all. Rather, RNAs could be forming complexes with proteins that are themselves modified by the sugars. The Stanford group added reagents to eat away at those complexes—but some complexes may have been resistant. Bertozzi declined to comment for this story, because she had submitted the manuscript to a peer-reviewed journal that asks authors not to comment before publication.
If it does turn out that cells are using enzymes to modify RNA with sugars, the big question is “why?” Among the possibilities: Sugars might help guide RNAs’ interactions with particular proteins or mark certain RNAs for removal. “We don’t know,” says Nicholas Conrad, an RNA biologist at UT Southwestern. “I just know that if this were happening in my lab, I would be really excited. It opens a whole new door we have to explore.”