Human DHX29 detects nonoptimal codon usage to regulate mRNA stability
- Fabian Hia
- Yitong Wu
- Masanori Yoshinaga
- Sakurako Goto-Ito
- Wakana Iwasaki
- Koshi Imami
- Hirotaka Toh
- Peixun Han
- Ting Cai
- Takayuki Ohira
- Akira Fukao
- Daron M. Standley
- Yuichi Shichino
- Masaki Takegawa
- Toshinobu Fujiwara
- Tsutomu Suzuki
- Shintaro Iwasaki
- Michael C. Bassik
- Takuhiro Ito
- Osamu Takeuchi
2026-03-19
Synonymous codon usage controls global gene expression in both prokaryotic and eukaryotic species. Nonoptimal codons are known to induce messenger RNA (mRNA) decay; however, the underlying molecular mechanism remains poorly understood in human cells. Through genome-wide CRISPR screening, we identified the RNA binding protein DHX29 as a critical regulator of codon-dependent gene expression. Cryo–electron microscopy and selective ribosome profiling demonstrated that DHX29 directly interacts with the A-site entrance of the translating 80 S ribosome, the binding site for the eEF1A•GTP•aminoacyl-tRNA ternary complex, suggesting a role in monitoring aminoacyl-tRNA sampling. Proteomic analysis further revealed that DHX29 recruits the GIGYF2•4EHP complex to mediate global suppression of nonoptimal mRNAs. These findings establish a mechanistic link between synonymous codon usage and the regulation of gene expression.