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This content will become publicly available on February 19, 2019

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

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.
Authors:
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)
Publication Date:
Grant/Contract Number:
AC02-76SF00515
Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 25; Journal Issue: 3; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1460737