2. Academic Validation
  3. RNA G-quadruplexes promote codon repeat-associated ribosomal frameshifting in human genes

RNA G-quadruplexes promote codon repeat-associated ribosomal frameshifting in human genes

  • Nucleic Acids Res. 2026 Jan 14;54(2):gkaf1481. doi: 10.1093/nar/gkaf1481.
Xiuwen Li 1 2,  Zhanbiao Li 1 2,  Yingshui Zhou 1 2,  Shimin Gong 1 2,  Zhenjing Chen 1 2,  Jingyang Li 1 2,  Miaomiao Guo 1 2,  Xiaoqian Gu 1 2,  Fei Li 1 2,  Jiayu Wei 1 2,  Tao Zhong 1 2,  Tong Yin 1 2,  Tianran Li 1 2,  Yu Xing 1 2,  Xiaomei Yang 1 2,  Limu Xu 1 2,  Fan Lai 1 2,  Yunkun Dang 1 2,  Guiping Ren 1 2
Affiliations

Affiliations

  • 1 Key Laboratory for Southwest Microbial Diversity of the Ministry of Education, Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Science, School of Life Sciences, Yunnan University, Kunming 650021, China.
  • 2 Southwest United Graduate School, Kunming 650092, China.
PMID: 41543171 DOI: 10.1093/nar/gkaf1481
Abstract

Programmed ribosomal frameshifting (PRF), a translational recoding process previously considered as a rare event in eukaryotes, has recently been demonstrated to occur extensively in humans. We have shown that codon repeats function as the signals for the production of trans-frame proteins in various human tissues. However, the molecular mechanism underlying this recoding process, termed codon repeat-associated ribosomal frameshifting (CRFS), remains largely unknown. In this study, we developed a reporter system by incorporating the CRFS sequence from histone deacetylase 1 (HDAC1), which directs efficient +1 ribosomal frameshifting at (UAC)3 repeats. Through a whole-genome CRISPR screening, we identified RBM4, an RNA-binding protein that interacts with RNA G-quadruplexes (rG4s), as an enhancer of ribosomal frameshifting in HDAC1 mRNA. Disruption of the rG4 immediately downstream of the (UAC)3 repeat region significantly reduces the frameshifting ratio, whereas application of rG4-stabilizing compounds or Other rG4 structures enhances frameshifting. Importantly, this rG4 sequence could insert into Other genes to significantly promote frameshifting efficiencies. As one of the critical elements for CRFS, our analysis suggests a significant enrichment of rG4s immediately downstream of codon repeats in the human genome, which could lead to ribosomal frameshifting in humans.

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