Weill Cornell Medicine team reveals long-standing mystery about mRNAs

A team of researchers at Weill Cornell Medicine in New York City has unraveled a decades-long mystery blanketing the purpose of some chemical modifications in messenger RNAs (mRNAs).

According to a report by Weill, the team found that mRNAs have a modification known as methylation, a key to the antiviral defense of cells. This modification provides the mRNA molecule with an extra layer of protection from antiviral immunities that could attack it. 

The findings were published in the Feb. 1 issue of Nature.

"We've known since the 1970s that methyl modifications are somehow fundamental to how mRNAs normally work,” said Dr. Samie Jaffrey, the Greenberg-Starr Professor in the Department of Pharmacology at Weill and senior author of the study. “It's very gratifying to finally have this insight into its precise role.”

According to the Cornell report, messenger RNAs are copied from active genes. They can carry instructions for the production of proteins from DNA in the cell nucleus to the cytosol, which is where they ultimately are turned into proteins.

The report noted that the team then examined exactly what the cells use to regulate mRNAs, including how they process their move switch into proteins, with one regulation relying on the incorporation of chemical modifications in mRNA. 

This, according to the report, can include methyl modifications. In other research, Jaffrey’s lab has derived ways to identify one of the methyl modifications, methyl adenosine (m6A), responsible for the stability of mRNA in cells, according to the report. 

Teaming with Vladimir Despic, a Ph.D and co-author of the study, Jaffrey looked at a key modification known as Cap 2, long a mystery, according to the university’s report.

To peel back the shroud of mystery, the report noted the researchers came up with CLAM-Cap-seq, a method to determine if Cap 2 methylation could happen on any mRNA or only mRNAs that have been in the cytosol for a longer term.

What they found surprised them, according to the report. They noted that Cap 1 reduces an mRNA’s ability to trigger cellular antiviral mechanisms, but Cap 2 provides extra protection.

This dance between Cap 1 and Cap 2 could portend some potential inflammatory or autoimmune disorders and could unlock treatment options for these issues.

“We think Cap 2 methylation occurs slowly, rather than quickly, in order to reduce the chance it will end up cloaking fast-replicating viral RNAs,” Jaffrey said in the university’s report.

Correcting the issues between Cap 1 and Cap 2 could lead to that treatment option. By inhibiting Cap 2, researchers contend, this could enhance antiviral immunity and ultimately boost mRNA-based medications, including vaccines, by limiting the inflammatory impact they have on cells.