Combinations of slow-translating codon clusters can increase mRNA half-life in Saccharomyces cerevisiae

Ajeet K. Sharma, Johannes Venezian, Ayala Shiber, Günter Kramer, Bernd Bukau, Edward P. O’Brien

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1 Scopus citations


The presence of a single cluster of nonoptimal codons was found to decrease a transcript’s half-life through the interaction of the ribosome-associated quality control machinery with stalled ribosomes in Saccharomyces cerevisiae. The impact of multiple nonoptimal codon clusters on a transcript’s half-life, however, is unknown. Using a kinetic model, we predict that inserting a second nonoptimal cluster near the 50 end can lead to synergistic effects that increase a messenger RNA’s (mRNA’s) half-life in S. cerevisiae. Specifically, the 50 end cluster suppresses the formation of ribosome queues, reducing the interaction of ribosome-associated quality control factors with stalled ribosomes. We experimentally validate this prediction by introducing two nonoptimal clusters into three different genes and find that their mRNA half-life increases up to fourfold. The model also predicts that in the presence of two clusters, the cluster closest to the 50 end is the primary determinant of mRNA half-life. These results suggest the “translational ramp,” in which nonoptimal codons are located near the start codon and increase translational efficiency, may have the additional biological benefit of allowing downstream slow-codon clusters to be present without decreasing mRNA half-life. These results indicate that codon usage bias plays a more nuanced role in controlling cellular protein levels than previously thought.

Original languageEnglish (US)
Article numbere2026362118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
StatePublished - Dec 21 2021

All Science Journal Classification (ASJC) codes

  • General


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