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Enhancing mRNA stability and translational potential through tailored modifications at the 3' end.

Olga Perzanowska1,2, Joanna Kowalska1, Jacek Jemielity2

  • 1Division of Biophysics, Faculty of Physics, University of Warsaw Pasteura 5 Warsaw 02-093 Poland Joanna.Kowalska@fuw.edu.pl.

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Summary

Chemically modified dinucleotides ligated to synthetic messenger RNA (mRNA) protect it from degradation. This 3' end engineering enhances protein production in cells, improving therapeutic mRNA candidates.

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Area of Science:

  • Molecular and Cellular Biology
  • Biochemistry
  • Synthetic Biology

Background:

  • Poly(A) tails on messenger RNA (mRNA) are crucial for regulating mRNA stability and translation.
  • Deadenylation, the shortening of the poly(A) tail, is the initial step in major mRNA decay pathways.
  • Protecting the 3' end of synthetic mRNA is vital for enhancing its therapeutic potential.

Purpose of the Study:

  • To develop a post-transcriptional strategy for protecting the 3' end of synthetic mRNA.
  • To investigate the use of enzymatically ligated, chemically modified dinucleotides for mRNA stabilization.
  • To assess the impact of 3'-end modification on mRNA deadenylation and translation efficiency.

Main Methods:

  • Enzymatic ligation of 5'-phosphorylated dinucleotides (2'-O-methyl and/or phosphorothioate modified) to model oligoadenylates and synthetic Gaussia luciferase (GLuc) mRNA using T4 RNA ligase 1.
  • In vitro deadenylation assays using human CNOT7 enzyme.
  • In vitro translation assays in rabbit reticulocyte lysate.
  • In vivo protein expression analysis in mammalian cell lines (A549, JAWSII, HEK293).

Main Results:

  • Ligated dinucleotide-modified mRNAs demonstrated significant resistance to CNOT7-mediated deadenylation in vitro compared to unmodified controls.
  • 3'-end modified GLuc mRNAs exhibited comparable translation efficiency in rabbit reticulocyte lysate to unmodified mRNA.
  • In mammalian cells, specific adenosine dinucleotide modifications (pApAm and pApsAm) enhanced cumulative GLuc production by up to 163% (HEK293) and 79% (A549).

Conclusions:

  • Dinucleotide ligation is an effective and modular strategy for engineering the 3' end of synthetic mRNA.
  • This approach enhances mRNA resistance to deadenylation, a key factor in mRNA decay.
  • 3'-end modification via dinucleotide ligation can significantly improve the translational performance of therapeutic mRNA candidates.