A study published in Cell reveals that the chemical modification N6-methyladenosine (m6A) on messenger RNAs plays a more active role in managing cellular stress responses than previously understood. Researchers at Weill Cornell Medicine have found that m6A tagging on mRNAs directs their degradation through a ribosome-mediated mechanism, an activity that halts during stress, allowing key stress-response proteins to be produced.
Although m6A has been associated with mRNA decay for decades, its mechanistic role in regulating translation and RNA stability during stress has remained unclear. The team, led by Samie Jaffrey and first author Shino Murakami, discovered that ribosomes do more than translate mRNA. When a ribosome encounters an m6A site during translation, it stalls. If another ribosome arrives before the first has moved past the mark, the resulting collision triggers the recruitment of m6A-binding proteins that target the transcript for degradation.
Under stress conditions, ribosomal activity slows, making such collisions less frequent. This pause in the degradation process allows m6A-marked mRNAs encoding stress-response proteins to accumulate and be translated. “We have known that m6A’s presence on a messenger RNA can induce its degradation, but we didn’t know that m6A’s powerful mRNA degradation effect was turned on and off to control cell physiology,” said Murakami.
The team identified this switch by analyzing large public datasets of mRNA profiles under diverse chemical treatments. Cells exposed to ribosome inhibitors consistently showed elevated levels of m6A-marked mRNAs, implicating translational machinery in the regulation.
The findings could have implications for current work in cancer trials. “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,” stated Jaffrey.
Publication Details
Murakami S, Olarerin-George AO, Liu JF, Zaccara S, Hawley B, Jaffrey SR. m6A alters ribosome dynamics to initiate mRNA degradation. Cell. 2025;doi:10.1016/j.cell.2025.04.020.
Although m6A has been associated with mRNA decay for decades, its mechanistic role in regulating translation and RNA stability during stress has remained unclear. The team, led by Samie Jaffrey and first author Shino Murakami, discovered that ribosomes do more than translate mRNA. When a ribosome encounters an m6A site during translation, it stalls. If another ribosome arrives before the first has moved past the mark, the resulting collision triggers the recruitment of m6A-binding proteins that target the transcript for degradation.
Under stress conditions, ribosomal activity slows, making such collisions less frequent. This pause in the degradation process allows m6A-marked mRNAs encoding stress-response proteins to accumulate and be translated. “We have known that m6A’s presence on a messenger RNA can induce its degradation, but we didn’t know that m6A’s powerful mRNA degradation effect was turned on and off to control cell physiology,” said Murakami.
The team identified this switch by analyzing large public datasets of mRNA profiles under diverse chemical treatments. Cells exposed to ribosome inhibitors consistently showed elevated levels of m6A-marked mRNAs, implicating translational machinery in the regulation.
The findings could have implications for current work in cancer trials. “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,” stated Jaffrey.
Publication Details
Murakami S, Olarerin-George AO, Liu JF, Zaccara S, Hawley B, Jaffrey SR. m6A alters ribosome dynamics to initiate mRNA degradation. Cell. 2025;doi:10.1016/j.cell.2025.04.020.