Human DHX29 detects nonoptimal codon usage to regulate mRNA stability

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Synonymous codon usage influences global gene expression in prokaryotes and eukaryotes.
• Nonoptimal codons are known to trigger mRNA decay, but the mechanism in human cells is unclear.

Purpose of the Study:

• To identify the molecular mechanism regulating codon-dependent gene expression in human cells.
• To elucidate the role of RNA-binding proteins in this process.

Main Methods:

• Genome-wide CRISPR screening to identify key regulators.
• Cryogenic electron microscopy and selective ribosome profiling to study protein-ribosome interactions.
• Proteomic analysis to identify interacting protein complexes.

Main Results:

• The RNA-binding protein DHX29 was identified as a critical regulator of codon-dependent gene expression.
• DHX29 directly interacts with the 80S ribosome's A-site, suggesting a role in monitoring aminoacyl-tRNA sampling.
• DHX29 recruits the GIGYF2•4EHP complex to suppress nonoptimal mRNAs globally.

Conclusions:

• DHX29 acts as a key mediator linking synonymous codon usage to gene expression regulation.
• This study establishes a mechanistic link between codon bias and mRNA regulation in human cells.