A tiny chemical modification commonly found on messenger RNAs plays a surprisingly large role in how cells respond to stress, according to a study led by Weill Cornell Medicine investigators. The finding clarifies an important aspect of cell biology, and may have clinical implications, since this messenger RNA modification, known as m6A, is the target of an emerging class of cancer treatments.
Messenger RNA (mRNA)—the molecule that carries genetic instructions to make proteins—is often marked with m6A, a chemical modification that acts like a "disposal tag." Cell-survival and other stress-response messenger RNAs often contain many more m6As than average messenger RNAs. Under normal conditions, this tag helps break down these messenger RNAs, keeping stress-response proteins at low levels.
In the study, published May 5 in Cell, the researchers uncovered surprising details of how this all works. They discovered that m6A triggers mRNA disposal while the mRNA is being read by the ribosome, the cellular machine that converts the instructions in mRNA into specific proteins. They found that the ribosome does more than just read the mRNA – it searches for m6A on the molecule and ensures that mRNAs with the modification are targeted for degradation. The scientists then found that this disposal process was put on hold when the cell is stressed—allowing stress-response messenger RNAs to accumulate and produce proteins that help the cell recover.
"These findings answer fundamental questions about m6A, in ways that are going to shift how we think about its roles in cell stress responses and cancers," said study senior author Dr. Samie Jaffrey, the Greenberg-Starr Professor in the Department of Pharmacology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
That messenger RNAs frequently contain m6A has been known since the 1970s, but the modification has started to come into focus only in the past several years, and many important questions remain unresolved.
"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 study first author Dr. Shino Murakami , an instructor in pharmacology at Weill Cornell Medicine.
The researchers initially suspected that some cellular pathway must turn off the degradation effect of m6A during cellular stress. To find an off switch, the researchers examined an extensive public database that documents how mRNA levels change in cells after they are exposed to many diverse types of chemicals and treatments. They found that cells that were exposed to compounds that inhibit ribosomes had unusually high levels of m6A-containing messenger RNAs, which are normally low. This implicated the ribosome in the process of degrading mRNAs with m6A.
This realization led them to the discovery of an unexpected series of events: They found that the ribosome essentially stops when it encounters an m6A on a messenger RNA. In normal cell conditions, another ribosome may come along on the same RNA before the first one moves past the m6A, causing the two ribosomes to collide. These "accidents" are in fact meaningful events, attracting m6A-reading proteins that initiate the disposal of the RNA. In this way, stress-response proteins encoded by m6A-modified mRNAs are mostly prevented from being produced under normal, non-stress conditions.
On the other hand, during periods of cell stress, when ribosomal activity typically is reduced, fewer ribosomes are available to collide. Thus, m6A-containing mRNAs accumulate and can be converted into stress response proteins.
"The m6A pathway normally helps suppress stress responses in cells, but we knew there has to be a switch that turns it off during cell stress, and it turns out the ribosome is a critical element of that switch," Dr. Jaffrey said.
The findings may have implications for cancer therapies. The emerging field of anti-m6A treatments, which work by inhibiting METTL3, the enzyme that catalyzes the formation of m6A on mRNAs, are being tested in clinical trials. This study raises the possibility that these drugs work by inducing the expression of stress response proteins, which are known to block the growth of certain cancer cells.
"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," Dr. Jaffrey said.
Dr. Samie Jaffrey is the co-founder, advisor, and/or has equity in Chimerna Therapeutics, 858 Therapeutics and Lucerna Technologies.
The research reported in this story was supported in part by the National Human Genome Research Institute and the National Institute of Neurological Disorders and Stroke, both part of the National Institutes of Health, and the NIH Office of the Director, through grant numbers RM1HG011563, R35NS111631 and S10OD030335.
