The ‘genetic-information survival strategies’ that viruses have mastered over millions of years of evolution have been elucidated on a large scale. These are regulatory principles that extend the lifespan of RNA and dramatically increase protein production, and they are expected to be used to enhance the performance of mRNA vaccines and therapeutics.
 [코리안투데이] A schematic diagram of how a linear mRNA with an applied tailon sequence achieves improved stability © 장형임 기자 |
The Ministry of Science and ICT (Deputy Prime Minister and Minister of Science and ICT Bae Kyung-hoon) announced that a research team led by V. Narry Kim, director of the RNA Research Center at the Institute for Basic Science (IBS, President Chang Suk-bok) and Distinguished Professor at Seoul National University, conducted a large-scale analysis of 337 species of viruses across 297 genera that infect vertebrates, uncovering various regulatory elements that enhance RNA stability and protein production and clarifying how they work. The findings were published in Cell, one of the world’s most prestigious journals, at midnight on August 14 (Korean time).
Viruses, which carry very small genomes, have evolved to make precise use of the host cell’s RNA regulatory system in order to operate their genetic information efficiently. In particular, when the ‘poly(A) tail’ at the end of an mRNA, which is required for protein production, becomes short, the mRNA is readily degraded; viruses have developed strategies that use the host cell’s RNA-regulating enzymes to protect this tail. The poly(A) tail is a structure in which adenine (A), one of the four bases that make up RNA, is repeated in succession, and it contributes to the stability of mRNA.
The researchers sought to harness these viral strategies to improve the stability of mRNA vaccines and therapeutics. In earlier studies published in 2023 (Cell) and 2025 (Nature Biotechnology), they had discovered viral RNA-stabilizing elements and shown that applying them to therapeutic mRNA could enhance stability and protein production. However, those earlier studies focused on a limited number of viruses and individual elements, making it difficult to systematically grasp the regulatory strategies that diverse viruses have evolved.
In this study, the team synthesized the genomes of the 337 virus species divided into about 200,000 RNA fragments (tiles) and used a massively parallel analysis method to systematically examine the diversity, mechanisms of action, and evolutionary features of the regulatory elements. As a result, they confirmed that the previously known strategy of exploiting the TENT4 enzyme is far more widespread than expected. TENT4 is a cellular regulatory enzyme that forms a ‘mixed tail’ at the end of RNA, suppressing degradation and extending its lifespan. The researchers identified 23 regulatory elements that use TENT4 to boost RNA stability and protein production; these are distributed across 19 viral genera and, based on their sequence and structural features, were classified into at least six types. This shows that phylogenetically distant viruses have each independently evolved similar strategies that exploit the same host regulatory system.
Notably, many new regulatory elements that do not rely on TENT4 were also discovered. Among these, the researchers focused on ‘Pt1,’ which showed a powerful effect. Pt1 is an element found in the 3′ end regulatory region (UTR) of the genome of the eel picornavirus (Potamipivirus); it works by directly recruiting PAP, the enzyme that synthesizes the poly(A) tail, to re-extend the shortening tail. In other words, by continuously replenishing the RNA tail, it slows the degradation of the mRNA. The researchers named these elements, which exploit the host’s RNA tail-regulating enzymes to enhance stability and protein production, ‘tailons.’
To verify the actual effect, the researchers applied Pt1 to an ordinary ‘linear mRNA.’ Linear mRNA has open ends and is therefore prone to being destroyed by degradation enzymes within the cell. In the experiment, the tail of the linear mRNA fitted with Pt1 grew from 60 adenines to 194, and its intracellular lifespan (half-life) increased about threefold, from 7.6 hours to 23.1 hours. Its stability improved dramatically, reaching the level of ‘circular RNA,’ which is known to be the most stable.
This means that the advantages of linear mRNA, which is relatively easy to manufacture, can be preserved while securing stability comparable to that of circular RNA. As seen with COVID-19 vaccines, mRNA technology is rapidly expanding into vaccines and treatments for rare diseases and cancer, but securing the stability needed to sustain drug efficacy over a long period has remained a key challenge. This achievement is expected to serve as a stepping stone for overcoming that limitation and securing innovative technologies that enhance the performance of vaccines and therapeutics.
V. Narry Kim, director of the IBS research center, said, ‘This study is an achievement that has revealed, on a large scale, the sophisticated strategies by which viruses exploit the host cell’s RNA regulatory system,’ adding, ‘The regulatory elements we discovered will become powerful molecular tools that can overcome the limitations of existing mRNA therapeutic technologies and greatly enhance the durability of drug efficacy.’ Kim Sung-soo, head of the R&D Office at the Ministry of Science and ICT, said, ‘To lead cutting-edge bio research, a fundamental understanding of life is ultimately most important,’ and added, ‘We will steadily support basic science research that uncovers unknown principles, so that it can contribute to strengthening national scientific competitiveness and to the shared prosperity of humankind.’
This research was carried out through the Ministry of Science and ICT’s support program for IBS research centers and the Ministry of Education’s BK21 program, among others; researchers Seo Genie and Lee Chae-min served as co-first authors, and director V. Narry Kim served as corresponding author. Going forward, the team plans to elucidate the molecular mechanisms of which proteins each type of tailon binds to in order to function, to further verify the effect of improving mRNA therapeutic performance, and to apply the findings to the development of treatments for rare diseases and cancer.
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