N1-Methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation.

Autor: Monroe J; Department of Chemistry, University of Michigan, Ann Arbor, MI, USA., Eyler DE; Department of Chemistry, University of Michigan, Ann Arbor, MI, USA., Mitchell L; RNA and Genome Editing, New England Biolabs Inc., Ipswich, MA, USA., Deb I; Department of Biophysics, University of Michigan, Ann Arbor, MI, USA., Bojanowski A; Department of Chemistry, University of Michigan, Ann Arbor, MI, USA., Srinivas P; Department of Chemistry, Emory University, Atlanta, GA, USA., Dunham CM; Department of Chemistry, Emory University, Atlanta, GA, USA., Roy B; RNA and Genome Editing, New England Biolabs Inc., Ipswich, MA, USA., Frank AT; Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.; Department of Biophysics, University of Michigan, Ann Arbor, MI, USA.; Computational Chemistry, Arrakis Therapeutics, Waltham, MA, USA., Koutmou KS; Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. kkoutmou@umich.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 16; Vol. 15 (1), pp. 8119. Date of Electronic Publication: 2024 Sep 16.
DOI: 10.1038/s41467-024-51301-0
Abstrakt: The ribosome utilizes hydrogen bonding between mRNA codons and aminoacyl-tRNAs to ensure rapid and accurate protein production. Chemical modification of mRNA nucleobases can adjust the strength and pattern of this hydrogen bonding to alter protein synthesis. We investigate how the N1-methylpseudouridine (m 1 Ψ) modification, commonly incorporated into therapeutic and vaccine mRNA sequences, influences the speed and fidelity of translation. We find that m 1 Ψ does not substantially change the rate constants for amino acid addition by cognate tRNAs or termination by release factors. However, we also find that m 1 Ψ can subtly modulate the fidelity of amino acid incorporation in a codon-position and tRNA dependent manner in vitro and in human cells. Our computational modeling shows that altered energetics of mRNA:tRNA interactions largely account for the context dependence of the low levels of miscoding we observe on Ψ and m 1 Ψ containing codons. The outcome of translation on modified mRNA bases is thus governed by the sequence context in which they occur.
(© 2024. The Author(s).)
Databáze: MEDLINE
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