Researchers at Kyoto University and RIKEN report that human cells can detect “non-optimal” synonymous codons—alternative three-letter genetic instructions that encode the same amino acid but are translated less efficiently—and selectively suppress the corresponding mRNAs. In experiments described in Science, the team identifies the RNA-binding protein DHX29 as a central component of this codon-dependent control of gene expression.
Human genes are read in three-letter nucleotide units called codons, which direct cells to add specific amino acids when building proteins. Although multiple codons can encode the same amino acid, prior research has suggested these “synonymous” codons can behave differently: some are associated with more efficient translation and greater mRNA stability, while others—often described as non-optimal—are translated less efficiently and are more prone to degradation.
To investigate how human cells respond to these differences, a Kyoto University–RIKEN team led by Osamu Takeuchi and Takuhiro Ito conducted a series of experiments, beginning with a genome-wide CRISPR screen to identify regulators of codon-dependent gene expression. The screen pointed to DHX29, an RNA-binding protein, as a key factor.
Follow-up RNA sequencing indicated that when DHX29 is absent, mRNAs enriched in non-optimal codons increase in abundance, consistent with a role for DHX29 in suppressing or destabilizing those messages. The researchers also used cryo-electron microscopy to visualize DHX29 interacting with the 80S ribosome, and selective ribosome profiling suggested DHX29 is more frequently associated with ribosomes decoding non-optimal codons.
Additional proteomic analyses reported by the team found that DHX29 recruits the GIGYF2•4EHP complex, which can repress translation of target mRNAs. In a statement released with the findings, co-corresponding author Masanori Yoshinaga said the results point to a direct molecular link between synonymous codon choice and the control of gene expression in human cells.
The work, published in Science as “Human DHX29 detects nonoptimal codon usage to regulate mRNA stability,” adds to evidence that codon choice can function as a regulatory layer influencing gene output, and the researchers said they plan to further examine how this mechanism operates in health and disease.
