N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products

Kyusik Q. Kim, Bhagyashri D. Burgute, Shin Cheng Tzeng, Crystal Jing, Courtney Jungers, Junya Zhang, Liewei L. Yan, Richard D. Vierstra, Sergej Djuranovic, Bradley S. Evans, Hani S. Zaher

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Synthetic mRNA technology is a promising avenue for treating and preventing disease. Key to the technology is the incorporation of modified nucleotides such as N1-methylpseudouridine (m1Ψ) to decrease immunogenicity of the RNA. However, relatively few studies have addressed the effects of modified nucleotides on the decoding process. Here, we investigate the effect of m1Ψ and the related modification pseudouridine (Ψ) on translation. In a reconstituted system, we find that m1Ψ does not significantly alter decoding accuracy. More importantly, we do not detect an increase in miscoded peptides when mRNA containing m1Ψ is translated in cell culture, compared with unmodified mRNA. We also find that m1Ψ does not stabilize mismatched RNA-duplex formation and only marginally promotes errors during reverse transcription. Overall, our results suggest that m1Ψ does not significantly impact translational fidelity, a welcome sign for future RNA therapeutics.

Original languageEnglish
Article number111300
JournalCell Reports
Volume40
Issue number9
DOIs
StatePublished - Aug 30 2022

Keywords

  • CP: Molecular biology
  • N1-methylpseudouridine
  • decoding
  • fidelity
  • mRNA vaccine
  • ribosome
  • translation

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