N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting

Abstract In vitro-transcribed (IVT) mRNAs are modalities that can combat human disease, exemplified by their use as vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IVT mRNAs are transfected into target cells, where they are translated into recombinant protein, and the biological activity or immunogenicity of the encoded protein exerts an intended therapeutic effect 1,2 . Modified ribonucleotides are commonly incorporated into therapeutic IVT mRNAs to decrease their innate immunogenicity 3–5 , but their effects on mRNA translation fidelity have not been fully explored. Here we demonstrate that incorporation of N 1 -methylpseudouridine into mRNA results in +1 ribosomal frameshifting in…

• WT
  Wellcome Trust

  Awards: 205228/Z/16/Z, WT109965MA
• UR
  UK Research and Innovation

  Awards: MR/X009297/1, NIHR200907
• NI
  National Institute for Health Research Health Protection Research Unit

  Award: NIHR200907
• NI
  National Institute for Health and Care Research

  Awards: NIHR300791, WT109965MA, NIHR203312, NIHR200907
• DO
  Department of Health and Social Care
• UC
  UK Coronavirus Immunology Consortium
• MR
  Medical Research Council

  Awards: MR/X009297/1, MC_UU_00025, NIHR203312, MC_PC_24008, MR/X009297/1, MC_UU_00025/8, MR/W02067X/1, MC_UU_00025/7, MC_UU_00025/12, MC_UU_00025/7
• NC
  NIHR Cambridge Biomedical Research Centre

  Award: NIHR203312