A small chemical tag on RNA molecules, known as m6A, has emerged as a powerful regulator of gene expression. Now, researchers from Weill Cornell Medicine report in Cell that this modification doesn’t just flag RNA molecules for destruction, but acts as a sophisticated molecular switch that integrates translation dynamics with stress signaling.
“Our study shows that m6A markedly alters ribosome dynamics and these alterations mediate the destabilizing effect of m6A on mRNA,” the authors wrote.
A ribosome-triggered disposal pathway
Messenger RNA (mRNA) is the molecular script for building proteins. Many mRNAs, especially those involved in stress responses, carry m6A tags. These tags mark them for degradation to maintain low protein levels in unstressed cells.
What this new study reveals is how that degradation process works: m6A causes the ribosome, the cell’s protein-making machine, to stall. When a second ribosome bumps into the stalled one, it creates a structure known as a disome. This collision is a signal: it recruits m6A “reader” proteins from the YTHDF family, which then trigger mRNA breakdown.
“m6A is a potent inducer of ribosome stalling,” the team reported, and “these stalls lead to ribosome collisions that form a unique conformation unlike those seen in other contexts.”
Interestingly, not all m6A tags trigger the same level of degradation. The researchers found that m6A-induced degradation is strongest when the tag is located within the coding region (CDS) of an mRNA, where ribosomes are actively reading. Tags in untranslated regions like the 3′ UTR have a weaker effect.
Putting the brakes on breakdown during stress
During cellular stress, such as nutrient depletion or endoplasmic reticulum stress, ribosome activity slows. This gives tagged mRNAs a reprieve. “Translation suppression during cell stress stabilizes m6A-mRNAs for stress responses,” the study noted.
Under these conditions, ribosomes are less likely to collide, so the degradation machinery doesn’t get recruited. This allows previously suppressed stress-response mRNAs to accumulate and be translated, helping the cell adapt and survive.
The researchers further demonstrated that impairing m6A-mediated degradation alone, by knocking out the METTL3 enzyme, was sufficient to activate autophagy, a key stress survival mechanism.
Implications for cancer therapy
Drugs that inhibit METTL3, the enzyme that adds m6A to mRNA, are currently being tested in clinical trials for cancer. The new findings suggest these treatments might work by allowing stress-response genes to stay active, thus interfering with cancer cell proliferation.
“Our new discovery suggests strategies for predicting the types of cancers that will respond to METTL3 inhibitors, which could help us identify the patients who will respond best to this therapy,” said study senior author Samie Jaffrey, MD, PhD, the Greenberg-Starr Professor in the Department of Pharmacology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, in a press release.
This work positions the ribosome not just as a passive reader of mRNA, but as an active sensor, deciding, in concert with m6A tags and YTHDF proteins, which messages get silenced and which survive to guide the cell’s fate. As efforts to target the m6A machinery move forward, understanding this regulatory nuance could be critical to designing smarter therapies.
