F or the first time, scientists have found that complex sugars called glycans may bind to some RNA molecules, according to a bioRxiv preprint published September 30. The findings could substantially alter the current perception of RNA’s function.
“There really is no framework in biology as we know it today that would explain how RNA and glycans could ever be in the same place at the same time, much less be connected to each other,” senior author Carolyn Bertozzi, a chemical biologist at Stanford University, tells The Scientist.
Bertozzi’s lab found the sugars attached to RNA while studying glycosylation, a reaction where sugar molecules are attached to proteins or other organic molecules, in a human cell line. Glycosylation has many functions, including helping proteins fold and cells adhere to one another, and is the mechanism behind different blood types. First author Ryan Flynn, a postdoc in Bertozzi’s lab, was trying to label glycoproteins when he spotted what seemed to be a glycan attached to RNA, a surprising finding that the researchers had never seen before. Further investigations determined that sugars called N-linked glycans were sticking to a subset of noncoding RNA molecules including small Y RNAs, which may have a role in DNA replication.
“It was a really weird discovery. At first we were skeptical. . . We tried to shoot it down in every way that we could think of, and it just kept holding up,” says Bertozzi.
They tried to separate out any proteins from the sample, but after a variety of treatments found that the sample was only sensitive to enzymes that cut up RNA. “We were kind of left with the answer that it was RNA,” Flynn tells The Scientist. Further research suggested that this RNA, which the researchers have termed glycoRNA, is also found in mouse and hamster cell cultures and in cells that were taken from living mice.
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The researchers don’t yet know how the RNA and the sugars are bound, because it was impossible to separate the two biopolymers except by using enzymes to digest either the RNA or the sugar. They believe the RNA and glycan “are somehow connected together through some linkage that is not a protein, or at least not a protein that’s recognized by a protease,” says Bertozzi, adding that the connection could be formed directly by covalent bonds.
RNA is normally found only in the nucleus and cytosol of cells, while glycosylation is thought to occur in the endoplasmic reticulum and Golgi bodies. For the two biopolymers to be found together, either RNA or glycans must enter one of these cell compartments in a way that was previously undetected, or there may be a molecule that acts as a go-between. “Whatever it is, it’s a completely unknown biology,” says Bertozzi.
Many of the glycoRNAs that were observed are known to contain RNAs that antibodies bind to in autoimmune conditions such as lupus. It is currently unknown why these RNAs might provoke an immune response.
Other RNA researchers expressed excitement about the paper and urged more research. “This paper, if verified, would certainly open up an entirely new direction of research investigating gene expression, gene regulation, quality control of transcription, and RNA turnover,” Richard Cummings, a professor of surgery at Harvard Medical School and the director of the National Center for Functional Glycomics who was not involved with the study, tells The Scientist.
“I was surprised and excited to see it. It’s an unexpected and thought-provoking observation,” says Torsten Krude at the University of Cambridge, a Y RNA researcher who was also not involved with the work. “If the results are consistent and verified by others, and if it holds the test of time and scrutiny, it would be an exciting new aspect to RNA biology.”
Bertozzi and Flynn have received feedback from other researchers since they announced the preprint on Twitter. “I think the more input we get, the better job we’ll be able to do to dig deeper and get to the bottom of this,” says Bertozzi.
R.A. Flynn et al., “Mammalian Y RNAs are modified at discrete guanosine residues with N-glycans,” bioRxiv, doi.org/10.1101/787614, 2019.
Emily Makowski is an intern at The Scientist. Email her at firstname.lastname@example.org.