Modulation of translational decoding by m6A modification of mRNA

Sakshi Jain, Lukasz Koziej, Panagiotis Poulis, Igor Kaczmarczyk, Monika Gaik, Michal Rawski, Namit Ranjan, Sebastian Glatt () and Marina V. Rodnina ()
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Sakshi Jain: Max Planck Institute for Multidisciplinary Sciences
Lukasz Koziej: Jagiellonian University
Panagiotis Poulis: Max Planck Institute for Multidisciplinary Sciences
Igor Kaczmarczyk: Jagiellonian University
Monika Gaik: Jagiellonian University
Michal Rawski: Jagiellonian University
Namit Ranjan: Max Planck Institute for Multidisciplinary Sciences
Sebastian Glatt: Jagiellonian University
Marina V. Rodnina: Max Planck Institute for Multidisciplinary Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract N6-methyladenosine (m6A) is an abundant, dynamic mRNA modification that regulates key steps of cellular mRNA metabolism. m6A in the mRNA coding regions inhibits translation elongation. Here, we show how m6A modulates decoding in the bacterial translation system using a combination of rapid kinetics, smFRET and single-particle cryo-EM. We show that, while the modification does not impair the initial binding of aminoacyl-tRNA to the ribosome, in the presence of m6A fewer ribosomes complete the decoding process due to the lower stability of the complexes and enhanced tRNA drop-off. The mRNA codon adopts a π-stacked codon conformation that is remodeled upon aminoacyl-tRNA binding. m6A does not exclude canonical codon-anticodon geometry, but favors alternative more dynamic conformations that are rejected by the ribosome. These results highlight how modifications outside the Watson-Crick edge can still interfere with codon-anticodon base pairing and complex recognition by the ribosome, thereby modulating the translational efficiency of modified mRNAs.

Date: 2023
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DOI: 10.1038/s41467-023-40422-7

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