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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)208-216
Number of pages9
JournalNature Structural and Molecular Biology
Volume25
Issue number3
DOIs
StatePublished - 1 Mar 2018

Funding

FundersFunder number
Ernest and Bonnie Beutler Research Program
Kahn Family Foundation
NSF Science and Technology CentersNSF-1231306
Office of Biological and Environmental Research
US Department of Energy
US National Institute of General Medical Sciences
US National Institutes of Health
US Office of Basic Energy Sciences
National Institutes of HealthGM51266
Howard Hughes Medical Institute
National Institute of General Medical SciencesR01GM113078
Human Frontier Science Program
Flight Attendant Medical Research Institute
University at Albany
Iowa Science Foundation
Israel Science Foundation41/11, 1796/12
Knut och Alice Wallenbergs Stiftelse
Vetenskapsrådet
Israeli Centers for Research Excellence

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