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Pseudouridine occurs naturally in some RNAs. But what about the methylated variant of it, N1-methyl-pseudouridine? The latter is a key ingredient in both the Pfizer and Moderna Covid-19 vaccines, probably due to its relative "potency" in evading immunogenicity to exogenous mRNA itself and its ability to apparently put ribosomes in a sort of "overdrive". (It's use in mRNA therapeutics has been patented by Moderna in 2012 or so.)

Does N1-methyl-pseudouridine occur naturally, in particular, does it occur in RNA?

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2 Answers 2

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N1-methyl-pseudouridine occurs naturally in the tRNAs of most archaea. It replaces the ribothymidine found in the TΨC-loop of eubacterial and eukaryotic tRNAs.

Comparison of tRNAs

Although the enzyme responsible for the conversion of uridine to pseudouridine has been known for some time, it is only relatively recently (2012) that the gene for the methylation of the pseudouridine was reported in a paper, the introduction to which provides a useful background to the topic.

Original References

Pang, H. et al. (1962) J.Biol.Chem. 257 3589-3593
Gupta, R. (1964) J.Biol.Chem. 259 9461-9471

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These articles claim it occurs naturally:

Pederson, A layperson encounter, on the “modified” RNA world:

Ironically as to my friend’s concern, N1-methylpseudouridine also occurs naturally (11), a final element in my “case” to him.

N1-Methylpseudouridine substitution enhances the performance of synthetic mRNA switches in cells:

Lastly, as a naturally existing modified base in both prokaryotic (37) and eukaryotic cells (38), our findings imply that m1Ψ might play unique roles in cells.

Both are referencing this paper:

which finds 1-methylpseudouridine in the ribosomal RNA of yeast and human-descended HeLa cells. (However, if I understand correctly, this is only a precursor molecule that exists temporarily and is then modified further?)

This one is a little more detailed:

Morais The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines

One N1-modified Ψ-derivative is N1-methyl-Ψ, a naturally occurring modification found in 18S rRNA (Brand et al., 1978) and tRNA in many organisms (Boccaletto et al., 2018). This N1-methylation is catalyzed by N1-specific Ψ methyltransferase Nep1 found in archaea and eukaryotes (Wurm et al., 2010) (Figure 1). Potentially N1-methyl-Ψ could be more widespread than reported in human RNA, given that the current standard Ψ-detection (-seq) methods, which rely on the use of CMC-modification followed by primer extension (Morais et al., 2021), may not be able to distinguish N1-methyl-Ψ from Ψ (Svitkin et al., 2017). Possibly, therefore, some Ψs thus identified so far (Schwartz et al., 2014) could actually be N1-methylated Ψs.

The Boccaletto reference is presumably this database entry:

which says

Found in phylogeny Archaea, Eukaryota
Found naturally in RNA types rRNA, tRNA

and Naturally occurring modified ribonucleosides shows Euler diagrams of m1Ψ occurring in

  • Archaea tRNA
  • Eukarya rRNA
  • but not in mRNA or ncRNA
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