Human DNA is constructed from long three-letter sequences of four nucleotides. These units, known as codons, tell cells which amino acids to use when building proteins. Although several different codons can code for the same amino acid, this is often considered simple redundancy in genetic systems.
However, research is increasingly revealing that these so-called synonymous codons are not truly equivalent. Some codons make the mRNA molecule more stable, making it easier for cells to translate it into protein and increasing its efficiency. Others that are considered suboptimal are more likely to be translated weakly and broken down. Until now, scientists did not fully understand how human cells recognize and respond to these inefficient codons.
Scientists explore cell ‘quality control’ systems
To investigate this question, a research team from Kyoto University and RIKEN, led by Osamu Takeuchi and Takuhiro Ito, conducted a series of experiments aimed at determining how cells process codon efficiency.
They started with a genome-wide CRISPR screen to identify factors involved in codon-dependent gene expression. This approach pointed to an important role for an RNA-binding protein called DHX29. Follow-up RNA-seq allowed the researchers to examine overall mRNA activity and revealed that loss of DHX29 resulted in a large increase in mRNA containing suboptimal codons.
How DHX29 detects and suppresses weak genetic messages
Using cryo-electron microscopy, the research team was able to observe how DHX29 physically interacts with the 80S ribosome, the cellular machinery responsible for protein production. Additional analysis using selective ribosome profiling showed that DHX29 is likely to bind ribosomes reading suboptimal codons.
Further proteomic studies revealed that DHX29 recruits the GIGYF2·4EHP protein complex. This complex acts to selectively suppress mRNAs containing suboptimal codons, effectively reducing the production of inefficient genetic messages.
“Taken together, these findings reveal a direct molecular link between synonymous codon selection and the regulation of gene expression in human cells,” said co-author Masanori Yoshinaga.
A new layer of gene regulation with broad implications
These discoveries are changing the way scientists think about gene regulation and show that codon choice itself plays a direct role in controlling gene expression in human cells. DHX29-mediated mechanisms can influence important biological processes such as cell differentiation, maintenance of cellular balance, and cancer development, suggesting widespread importance.
The researchers plan to continue investigating how DHX29 affects gene activity in both health and disease.
“We have long been interested in how cells interpret hidden layers of information embedded in the genetic code, so discovering the molecular factors that enable human cells to read and respond to this hidden code was particularly rewarding,” says team leader Osamu Takeuchi.
