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<p>Several approaches exist to silence genes, but few tools are available to activate individual mRNAs for translation inside cells. Guiding ribosomes to specific start codons without altering the original sequence remains a formidable task. Here we design capped <i>trans</i>-RNAs capable of directing ribosomes to specific initiation sites on individual mRNAs when the <i>trans</i>-cap is positioned near the target start codon. Structural and biochemical data suggest that the capped <i>trans</i>-RNA facilitates ribosome loading and scanning on the target mRNA through a synergistic mechanism involving alternative cap recognition. The <i>trans</i>-RNA also acts independently of the cap on the target mRNA, enabling translation of circular RNAs lacking internal ribosome entry sites. We apply <i>trans</i>-RNAs in vivo to achieve programmable alternative translation of endogenous genes in mouse liver. Finally, we provide the evidence for the existence of natural transcripts that, similarly to exogenous <i>trans</i>-RNAs, activate translation of endogenous mRNAs.</p>

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Programmable initiation of mRNA translation by trans-RNA

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Longfei Jia,
  • Tan-Trung Nguyen,
  • Saori Uematsu,
  • Yifei Gu,
  • Shengcho Shi,
  • Yaser Hashem,
  • Shu-Bing Qian

摘要

Several approaches exist to silence genes, but few tools are available to activate individual mRNAs for translation inside cells. Guiding ribosomes to specific start codons without altering the original sequence remains a formidable task. Here we design capped trans-RNAs capable of directing ribosomes to specific initiation sites on individual mRNAs when the trans-cap is positioned near the target start codon. Structural and biochemical data suggest that the capped trans-RNA facilitates ribosome loading and scanning on the target mRNA through a synergistic mechanism involving alternative cap recognition. The trans-RNA also acts independently of the cap on the target mRNA, enabling translation of circular RNAs lacking internal ribosome entry sites. We apply trans-RNAs in vivo to achieve programmable alternative translation of endogenous genes in mouse liver. Finally, we provide the evidence for the existence of natural transcripts that, similarly to exogenous trans-RNAs, activate translation of endogenous mRNAs.