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<p>Endogenous uridine-rich small nuclear RNAs (U snRNAs) form RNA–protein complexes to process eukaryotic pre-mRNA into mRNA. Previous studies have demonstrated programmable U snRNA guide-targeted exon inclusion and exclusion. Here we investigated whether snRNAs can also enhance RNA base editing over state-of-the-art RNA-targeting technologies in human cells. Compared with adenosine deaminase acting on RNA (ADAR)-recruiting circular RNAs, we find that guided A&gt;I snRNAs consistently increase adenosine-to-inosine editing for higher exon count genes, perturb substantially fewer off-target genes and localize more persistently to the nucleus where ADAR is expressed. A&gt;I snRNAs also more efficiently edit long noncoding RNAs and pre-mRNA 3′ splice sites to promote splicing changes. Lastly, snRNA–H/ACA box snoRNA fusions (U&gt;Ψ snRNAs) increase targeted RNA pseudouridylation without DKC1 overexpression, facilitating improved <i>CFTR</i> rescue from nonsense-mediated mRNA decay in a cystic fibrosis human bronchial epithelial cell model. Our results advance the endogenous protein-mediated RNA base editing toolbox and RNA-targeting technologies to treat genetic diseases.</p><p></p>

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Enhancing RNA base editing on mammalian transcripts with small nuclear RNAs

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月18日

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  • Aaron A. Smargon,
  • Deepak Pant,
  • Trent A. Gomberg,
  • Christian Fagre,
  • Sofia Glynne,
  • Johnathan Nguyen,
  • Jack T. Naritomi,
  • Wendy V. Gilbert,
  • Gene W. Yeo

摘要

Endogenous uridine-rich small nuclear RNAs (U snRNAs) form RNA–protein complexes to process eukaryotic pre-mRNA into mRNA. Previous studies have demonstrated programmable U snRNA guide-targeted exon inclusion and exclusion. Here we investigated whether snRNAs can also enhance RNA base editing over state-of-the-art RNA-targeting technologies in human cells. Compared with adenosine deaminase acting on RNA (ADAR)-recruiting circular RNAs, we find that guided A>I snRNAs consistently increase adenosine-to-inosine editing for higher exon count genes, perturb substantially fewer off-target genes and localize more persistently to the nucleus where ADAR is expressed. A>I snRNAs also more efficiently edit long noncoding RNAs and pre-mRNA 3′ splice sites to promote splicing changes. Lastly, snRNA–H/ACA box snoRNA fusions (U>Ψ snRNAs) increase targeted RNA pseudouridylation without DKC1 overexpression, facilitating improved CFTR rescue from nonsense-mediated mRNA decay in a cystic fibrosis human bronchial epithelial cell model. Our results advance the endogenous protein-mediated RNA base editing toolbox and RNA-targeting technologies to treat genetic diseases.