通过全基因组CRISPR筛选，研究团队发现RNA结合蛋白DHX29是密码子依赖性基因表达的关键调控因子。低温电子显微镜和选择性核糖体分析表明，DHX29直接与翻译的80S核糖体的A位点入口相互作用，这是eEF1A三磷酸鸟苷氨基酰基-tRNA三元配合物，提示在监测氨基酰基-tRNA取样中的作用。蛋白质组学分析进一步揭示DHX29募集GIGYF24EHP复合物介导非最佳mRNA的全局抑制。这些发现建立了同义密码子图像与基因表达调控之间的机制联系。
研究人员表示，同义密码子序列控制着原核生物和真核生物物种的整体基因表达。已知非最佳密码子可诱导mRNA衰变；然而，在人类细胞中，潜在的分子机制仍然知之甚少。
附：英文原文
Title: Human DHX29 detects nonoptimal codon usage to regulate mRNA stability
Author: 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
Issue&Volume: 2026-03-19
Abstract: Synonymous codon usage controls global gene expression in both prokaryotic and eukaryotic species. Nonoptimal codons are known to induce 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. Cryogenic electron microscopy and selective ribosome profiling demonstrated that DHX29 directly interacts with the A-site entrance of the translating 80S ribosome, the binding site for the eEF1AGTPaminoacyl-tRNA ternary complex, suggesting a role in monitoring aminoacyl-tRNA sampling. Proteomic analysis further revealed that DHX29 recruits the GIGYF24EHP complex to mediate global suppression of nonoptimal mRNAs. These findings establish a mechanistic link between synonymous codon usage and the regulation of gene expression.
DOI: adw0288
Source: https://www.science.org/doi/10.1126/science.adw0288