Investigators at Weill Cornell Medicine recently published a study that shows just how important a small chemical addition, known as m6A (read “em six ay”), truly is. This PTM is a key player in the cellular stress response. On May 5, 2022, the journal Cell published research that demonstrates the major regulatory factor m6A plays in cellular stress response. This change, which has been known on messenger RNAs (mRNAs) since the 1970s, turns out to be more powerful than previously believed.
m6A functions like a “disposal tag” on mRNA. It pauses ribosomes elongation in elongation and controls overall protein synthesis dynamics during cellular stress conditions. The study’s findings demonstrate that this change effectively promotes mRNA degradation. It’s increasingly important in regulating how cells adapt to stress, which may point to new cancer therapeutic avenues — Read more.
Understanding m6A and Its Mechanism
m6A is a relatively new chemical modification that is added to specific locations on messenger RNAs and is deposited by an enzyme known as METTL3. Researchers have tried to make this change for decades. The consequences for cellular stress responses are just starting to be understood. Under typical cellular conditions, ribosomes should be able to freely translate mRNA into functional proteins without any pauses. In contrast, the presence of m6A can lead to ribosome collisions, decreasing the efficacy of protein synthesis.
Dr. Samie Jaffrey, senior author of the study and Greenberg-Starr Professor in Weill Cornell Medicine’s Department of Pharmacology. To start, he described how m6A mediates a positive and negative balance within cells. He stated, “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.”
This finding provides evidence that m6A initiates a domino effect resulting in mRNA degradation. In this way, their cells can focus their efforts where it matters most in times of stress.
Implications for Cancer Treatment
The therapeutic implications of deciphering m6A are deep, particularly in the realm of cancer therapy. Additional anti-m6A treatments that inhibit METTL3 are already undergoing testing in clinical trials. These innovative therapies seek to harness the m6A pathway to improve the effectiveness of cancer treatments. Dr. Jaffrey noted, “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.”
This study provides important insights into how m6A regulates the behavior of cells in response to stress. This knowledge is invaluable to the development of precision cancer therapies.
New Perspectives on Cell Physiology
Dr. Shino Murakami, the study’s first author, noted that the significance of these findings were not lost on them. “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.” This newly elucidated function does more than help explain m6A’s role in the body, it points to it as a promising therapeutic target.
Dr. Jaffrey summarized this sentiment by stating, “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.”