Human DNA is built from long sequences of three-letter units made up of four nucleotides. These units, known as codons, tell cells which amino acids to use when building proteins. While several different codons can code for the same amino acid, this has often been viewed as simple redundancy in the genetic system.
However, research is increasingly showing that these so-called synonymous codons are not truly equal. Some codons make mRNA molecules more stable and easier for cells to translate into proteins, making them more efficient. Others, considered non-optimal, lead to weaker translation and are more likely to be broken down. Until now, scientists have not fully understood how human cells recognize and respond to these less efficient codons.
Scientists Search for the Cell’s “Quality Control” System
To investigate this question, a research team from Kyoto University and RIKEN, led by Osamu Takeuchi and Takuhiro Ito, carried out a series of experiments aimed at uncovering how cells handle codon efficiency.
They began with a genome-wide CRISPR screening to identify factors involved in codon-dependent gene expression. This approach pointed to an RNA-binding protein called DHX29 as a key player. Follow-up RNA sequencing allowed the researchers to examine overall mRNA activity, revealing that when DHX29 is missing, mRNAs containing non-optimal codons increase in abundance.
How DHX29 Detects and Suppresses Weak Genetic Messages
Using cryo-electron microscopy, the 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 more likely to associate with ribosomes that are reading non-optimal codons.
Further proteomic studies revealed that DHX29 recruits the GIGYF2•4EHP protein complex. This complex acts to selectively suppress mRNAs that contain non-optimal codons, effectively reducing the production of inefficient genetic messages.
“Together, these findings reveal a direct molecular link between synonymous codon choice and the control of gene expression in human cells,” says co-corresponding author Masanori Yoshinaga.
A New Layer of Gene Regulation With Broad Implications
These findings change how scientists think about gene regulation, showing that codon choice itself plays a direct role in controlling gene expression in human cells. The DHX29-driven mechanism could influence important biological processes such as cell differentiation, maintaining cellular balance, and the development of cancer, suggesting wide-ranging significance.
The researchers plan to continue exploring how DHX29 affects gene activity in both health and disease.
“We have long been fascinated by how cells interpret the hidden layer of information embedded within the genetic code, so discovering the molecular factor that allows human cells to read and respond to this hidden code has been particularly rewarding,” says team leader Osamu Takeuchi.
