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Title: 2'-O-methylation in mRNA disrupts tRNA decoding during translation elongation

Journal Article · · Nature Structural & Molecular Biology
ORCiD logo [1];  [2]; ORCiD logo [3];  [2]; ORCiD logo [4];  [5];  [1];  [6];  [6]; ORCiD logo [7];  [2]; ORCiD logo [4]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States); Stanford Univ., Stanford, CA (United States)
  2. Uppsala Univ., Uppsala (Sweden)
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  4. Stanford Univ. School of Medicine, Stanford, CA (United States)
  5. Stanford Univ. School of Medicine, Stanford, CA (United States); Auburn Univ., Auburn, AL (United States)
  6. Chaim Sheba Medical Center, Tel-Hashomer (Israel); Tel Aviv Univ., Tel Aviv (Israel)
  7. The Univ. of Chicago, Chicago, IL (United States)

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. In conclusion, our current and prior findings highlight how chemical modifications of mRNA tune the dynamics of protein synthesis at different steps of translation elongation.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1460737
Journal Information:
Nature Structural & Molecular Biology, Vol. 25, Issue 3; ISSN 1545-9993
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 68 works
Citation information provided by
Web of Science

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Cited By (27)

RNA 2’-O-Methylation (Nm) Modification in Human Diseases journal February 2019
Above the Epitranscriptome: RNA Modifications and Stem Cell Identity journal June 2018
Eukaryotic Translation Elongation is Modulated by Single Natural Nucleotide Derivatives in the Coding Sequences of mRNAs journal January 2019
Dynamics of the context-specific translation arrest by chloramphenicol and linezolid text January 2021
Pseudouridinylation of mRNA coding sequences alters translation journal October 2019
Eukaryotic Translation Elongation is Modulated by Single Natural Nucleotide Derivatives in the Coding Sequences of mRNAs journal January 2019
AlkAniline‐Seq: Profiling of m 7 G and m 3 C RNA Modifications at Single Nucleotide Resolution journal December 2018
NmSEER: A Prediction Tool for 2’-O-Methylation (Nm) Sites Based on Random Forest book January 2018
Modification of messenger RNA by 2′-O-methylation regulates gene expression in vivo journal July 2019
The epitranscriptome in translation regulation: mRNA and tRNA modifications as the two sides of the same coin? journal June 2019
AlkAniline‐Seq: Profiling of m 7 G and m 3 C RNA Modifications at Single Nucleotide Resolution journal December 2018
Modification of messenger RNA by 2′-O-methylation regulates gene expression in vivo journal July 2019
The energy landscape of −1 ribosomal frameshifting journal January 2020
Dynamics of the context-specific translation arrest by chloramphenicol and linezolid journal December 2019
Importance of potassium ions for ribosome structure and function revealed by long-wavelength X-ray diffraction journal June 2019
The energy landscape of −1 ribosomal frameshifting journal January 2020
Functional Interplay between Small Non-Coding RNAs and RNA Modification in the Brain journal June 2018
Structural and molecular mechanisms for the control of eukaryotic 5′–3′ mRNA decay journal December 2018
Importance of potassium ions for ribosome structure and function revealed by long-wavelength X-ray diffraction journal June 2019
The roles of structural dynamics in the cellular functions of RNAs journal June 2019
A short translational ramp determines the efficiency of protein synthesis journal December 2019
A molecular‐level perspective on the frequency, distribution, and consequences of messenger RNA modifications journal January 2020
tRNA 2′-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila journal January 2020
RNA 2’-O-Methylation (Nm) Modification in Human Diseases journal February 2019
Above the Epitranscriptome: RNA Modifications and Stem Cell Identity journal June 2018
A short translational ramp determines the efficiency of protein synthesis journal December 2019
The epitranscriptome in translation regulation: mRNA and tRNA modifications as the two sides of the same coin? text January 2019

Figures / Tables (8)


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