Synonymous codon usage regulates translation initiation; Barrington et al.

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Abstract: Nonoptimal synonymous codon usage represses gene expression, but the underlying mechanisms are poorly understood. We and others have shown that nonoptimal codons slow translation elongation speeds and thereby trigger mRNA degradation. Nevertheless, transcript levels are often insufficient to explain protein levels, suggesting there are additional mechanisms by which codon usage regulates gene expression. Using reporter assays in human and Drosophila cells, we found that transcript levels account for less than half of the variation in protein abundance. This discrepancy is explained by translational differences whereby nonoptimal codons repress translation initiation. Nonoptimal transcripts are also less bound by the key translation initiation factors eIF4E and eIF4G, providing a mechanistic explanation for their reduced initiation rates. Importantly, translational repression can occur in the absence of mRNA decay and deadenylation, and it does not depend on the known nonoptimality sensor, CNOT3. Our results reveal a potent new mechanism of regulation by codon usage, where nonoptimal codons repress further rounds of translation. Raw images are included here, i.e. Western blots and microscopy images. They are organized by Figure.

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