Translation Readthrough Mitigation

Details

• Alternative Title:
  Nature
• Personal Author:
  Arribere, Joshua A. ; Cenik, Elif S. ; Jain, Nimit ; Hess, Gaelen T. ; Lee, Cameron H. ; Bassik, Michael C. ; Fire, Andrew Z.
• Description:
  A fraction of ribosomes engaged in translation will fail to terminate when reaching a stop codon, yielding nascent proteins inappropriately extended on their C termini. Although such extended proteins can interfere with normal cellular processes, known mechanisms of translational surveillance are insufficient to protect cells from potential dominant consequences. Here, through a combination of transgenics and CRISPR–Cas9 gene editing in Caenorhabditis elegans, we demonstrate a consistent ability of cells to block accumulation of C-terminal-extended proteins that result from failure to terminate at stop codons. Sequences encoded by the 3′ untranslated region (UTR) were sufficient to lower protein levels. Measurements of mRNA levels and translation suggested a co- or post-translational mechanism of action for these sequences in C. elegans. Similar mechanisms evidently operate in human cells, in which we observed a comparable tendency for translated human 3′ UTR sequences to reduce mature protein expression in tissue culture assays, including 3′ UTR sequences from the hypomorphic ‘Constant Spring’ haemoglobin stop codon variant. We suggest that 3′ UTRs may encode peptide sequences that destabilize the attached protein, providing mitigation of unwelcome and varied translation errors.
• Subjects:
  • 3' Untranslated Regions
  • Animals
  • Animals, Genetically Modified
  • CRISPR-Cas Systems
  • Caenorhabditis elegans
  • Codon, Terminator
  • Genes
  • Hemoglobins, Abnormal
  • Humans
  • Peptides
  More +
• Source:
  Nature. 534(7609):719-723
• Pubmed ID:
  27281202
• Pubmed Central ID:
  PMC5054982
• Document Type:
  Journal Article
• Funding:
  DP2 HD084069/HD/NICHD NIH HHSUnited States/ ; 1DP2HD084069-01/DP/NCCDPHP CDC HHSUnited States/ ; T32HG000044/HG/NHGRI NIH HHSUnited States/ ; F32 GM112474/GM/NIGMS NIH HHSUnited States/ ; R01GM37706/GM/NIGMS NIH HHSUnited States/ ; T32 HG000044/HG/NHGRI NIH HHSUnited States/ ; T32 GM007790/GM/NIGMS NIH HHSUnited States/ ; 5F32GM112474-02/GM/NIGMS NIH HHSUnited States/ ; R01 GM037706/GM/NIGMS NIH HHSUnited States/
• Volume:
  534
• Issue:
  7609
• Download URL:
  https://stacks.cdc.gov/view/cdc/41676/cdc_41676_DS1.pdf
• File Type:
  [PDF - 5.34 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:779fdfb1b10de65b00007276be704b8e561c808fcf47eea8e054b6e2daf12e79