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. Through a combination of transgenics and CRISPR/Cas9 gene editing in C. 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. 3’UTR-encoded sequences 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, where we observed a comparable tendency for translated human 3’UTR sequences to reduce mature protein expression in tissue culture assays, including 3' sequences from the hypomorphic “Constant Spring” hemoglobin stop codon variant. We suggest 3’UTRs may encode peptide sequences that destabilize the attached protein, providing mitigation of unwelcome and varied translation errors.
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