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Translation readthrough mitigation

2016; Nature Portfolio; Volume: 534; Issue: 7609 Linguagem: Inglês

10.1038/nature18308

1476-4687

Joshua A. Arribere, Elif Sarinay Cenik, Nimit Jain, Gaelen T. Hess, Cameron H. Lee, Michael C. Bassik, Andrew Fire,

RNA and protein synthesis mechanisms

Translation termination sequences are occasionally bypassed by the ribosome and the resulting proteins can be detrimental to the cell; here it is shown that cells can prevent such proteins from accumulating through peptides that are encoded within the 3' UTR of genes in both humans and C. elegans. Messenger RNAs contain stop sequences, but these are sometimes bypassed by the ribosome, leading to an extension at the C terminus of the protein. Such proteins are often detrimental to the cell, suggesting that there are surveillance mechanisms to detect and deal with these proteins. Using a combination of CRISPR–Cas9-mediated editing and transgenics, Andrew Fire and colleagues demonstrate that cells can prevent such proteins from accumulating, through peptides that are encoded within the 3' UTR of genes in both Caenorhabditis elegans and humans. Although the mechanism is not yet clear, these peptides are able to lower the levels of C-terminal-extended proteins, providing mitigation of unwelcome and varied translation errors. 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 surveillance1 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.