2′-O-methylation in mRNA disrupts tRNA decoding during translation elongation

Junhong Choi, Gabriele Indrisiunaite, Hasan Demirci, Ka Weng Ieong, Jinfan Wang, Alexey Petrov, Arjun Prabhakar, Gideon Rechavi, Dan Dominissini, Chuan He, Måns Ehrenberg, Joseph D. Puglisi

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Abstract

Chemical modifications of mRNA may regulate many aspects of mRNA processing and protein synthesis. Recently, 2′-O-methylation of nucleotides was identified as a frequent modification in translated regions of human mRNA, showing enrichment in codons for certain amino acids. Here, using single-molecule, bulk kinetics and structural methods, we show that 2′-O-methylation within coding regions of mRNA disrupts key steps in codon reading during cognate tRNA selection. Our results suggest that 2′-O-methylation sterically perturbs interactions of ribosomal-monitoring bases (G530, A1492 and A1493) with cognate codon-anticodon helices, thereby inhibiting downstream GTP hydrolysis by elongation factor Tu (EF-Tu) and A-site tRNA accommodation, leading to excessive rejection of cognate aminoacylated tRNAs in initial selection and proofreading. Our current and prior findings highlight how chemical modifications of mRNA tune the dynamics of protein synthesis at different steps of translation elongation.

LanguageEnglish (US)
Pages208-216
Number of pages9
JournalNature Structural and Molecular Biology
Volume25
Issue number3
DOIs
StatePublished - Mar 1 2018

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Transfer RNA
Methylation
Messenger RNA
Codon
Peptide Elongation Factor Tu
Anticodon
Guanosine Triphosphate
Reading
Proteins
Hydrolysis
Nucleotides
Amino Acids

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Choi, J., Indrisiunaite, G., Demirci, H., Ieong, K. W., Wang, J., Petrov, A., ... Puglisi, J. D. (2018). 2′-O-methylation in mRNA disrupts tRNA decoding during translation elongation. Nature Structural and Molecular Biology, 25(3), 208-216. https://doi.org/10.1038/s41594-018-0030-z

2′-O-methylation in mRNA disrupts tRNA decoding during translation elongation. / Choi, Junhong; Indrisiunaite, Gabriele; Demirci, Hasan; Ieong, Ka Weng; Wang, Jinfan; Petrov, Alexey; Prabhakar, Arjun; Rechavi, Gideon; Dominissini, Dan; He, Chuan; Ehrenberg, Måns; Puglisi, Joseph D.

In: Nature Structural and Molecular Biology, Vol. 25, No. 3, 01.03.2018, p. 208-216.

Research output: Contribution to journalArticle

Choi, J, Indrisiunaite, G, Demirci, H, Ieong, KW, Wang, J, Petrov, A, Prabhakar, A, Rechavi, G, Dominissini, D, He, C, Ehrenberg, M & Puglisi, JD 2018, '2′-O-methylation in mRNA disrupts tRNA decoding during translation elongation' Nature Structural and Molecular Biology, vol. 25, no. 3, pp. 208-216. https://doi.org/10.1038/s41594-018-0030-z
Choi, Junhong ; Indrisiunaite, Gabriele ; Demirci, Hasan ; Ieong, Ka Weng ; Wang, Jinfan ; Petrov, Alexey ; Prabhakar, Arjun ; Rechavi, Gideon ; Dominissini, Dan ; He, Chuan ; Ehrenberg, Måns ; Puglisi, Joseph D. / 2′-O-methylation in mRNA disrupts tRNA decoding during translation elongation. In: Nature Structural and Molecular Biology. 2018 ; Vol. 25, No. 3. pp. 208-216.
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