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N1-Methylpseudouridine directly modulates translation dynamics.

Batsheva Rozman1, Karin Broennimann2, K Shanmugha Rajan3

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Modified nucleosides like N¹-methylpseudouridine (m¹Ψ) boost synthetic mRNA protein production by directly influencing ribosome speed and initiation. This enhances translation efficiency in specific codon contexts.

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Area of Science:

  • Biomedical technology
  • Molecular biology
  • Synthetic biology

Background:

  • Synthetic messenger RNA (mRNA) technology has shown significant success, particularly in vaccines.
  • N¹-methylpseudouridine (m¹Ψ) is a key modified nucleoside used in synthetic mRNA to improve protein expression and reduce unwanted immune responses.
  • The precise mechanisms by which m¹Ψ influences mRNA translation are not fully understood.

Purpose of the Study:

  • To elucidate the detailed effects of m¹Ψ on mRNA translation dynamics at a subcodon level.
  • To investigate how m¹Ψ impacts ribosome movement, initiation, and overall protein output.
  • To determine the sequence-specific contexts where m¹Ψ exerts its strongest effects on translation.

Main Methods:

  • Ribosome profiling at subcodon resolution to analyze ribosome density and movement.
  • Cryo-electron microscopy to visualize structural changes induced by m¹Ψ in the ribosome.
  • Synonymous recoding strategies to probe the role of codon composition in m¹Ψ-mediated effects.

Main Results:

  • m¹Ψ increases ribosome density on synthetic mRNAs, leading to higher protein production.
  • m¹Ψ directly slows ribosome elongation in specific sequence contexts while promoting translation initiation.
  • Structural analysis reveals m¹Ψ alters ribosomal decoding center interactions, explaining the slowed elongation.
  • The enhancing effect of m¹Ψ on protein output is dependent on mRNA codon composition, particularly with non-optimal codons containing uridines.

Conclusions:

  • m¹Ψ directly modulates mRNA translation dynamics, enhancing protein yield.
  • The impact of m¹Ψ is context-dependent, influenced by specific mRNA sequences and codon usage.
  • These findings provide a mechanistic understanding of m¹Ψ's role in optimizing synthetic mRNA performance.