Gene expression is intricately controlled through various regulatory layers, spanning from transcription to post-translational modifications. In 1970, the discovery of RNA editing marked a pivotal moment in molecular biology, unveiling N6-methyladenosine (m6A) as the first identified RNA modification. Today, RNA editing stands as a crucial facet of gene regulation, contributing not only to our understanding of the genetic code and protein diversity but also to RNA stability and structure.
This field has rapidly gained momentum and is currently a focal point of scientific research. Just today, the Nobel assembly at Karolinska Institutet honored Drew Weissman and Katalin Karikó with the Nobel Prize in Physiology or Medicine for their groundbreaking work in RNA editing. Their research laid the foundation for the development of highly effective mRNA vaccines against COVID-19.
Understanding how cells distinguish between host and foreign RNA is a fundamental question. Toll-like receptors (TLRs) play a key role in this process. While there are various mechanisms, one significant factor is differential modification patterns. Most eukaryotic RNAs undergo editing, preventing them from triggering an immune response. Conversely, unmodified RNAs elicit an immune response. Karikó and Weissman demonstrated that introducing RNA modifications, such as 5-methylcytosine (m5C), m6A, 5-methyluridine (m5U), pseudouridine (Ψ), or 2’-O-methyl-U, can attenuate or eliminate the immune response. they also showed that pseudouridine enhances mRNA translation efficiency.
Vaccine companies have harnessed this knowledge, incorporating these modifications into mRNA vaccines. Pfizer-BioNTech and Moderna, for instance, added N1-methyl-pseudouridine to their vaccines, yielding remarkable results in pandemic control. The modifications prevented any kind of inflammatory response.
During the COVID-19 crisis, the RNA modifications field played a pivotal role, saving millions of lives. As RNA therapeutics continue to advance rapidly, the RNA editing field has emerged as a scientific hotspot. Beyond therapeutics, this area of research holds the potential to answer profound questions about evolution and the genetic code’s diversity.
References:
1. Karikó, K., Buckstein, M., Ni, H., and Weissman, D. (2005). Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA. Immunity 23, 165–175. 10.1016/j.immuni.2005.06.008.
2. Anderson, B.R., Muramatsu, H., Nallagatla, S.R., Bevilacqua, P.C., Sansing, L.H., Weissman, D., and Karikó, K. (2010). Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res 38, 5884–5892. 10.1093/nar/gkq347.
3. Morais, P., Adachi, H., and Yu, Y.-T. (2021). The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines. Frontiers in Cell and Developmental Biology 9.
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