4.8 Article

Programmable RNA base editing with a single gRNA-free enzyme

期刊

NUCLEIC ACIDS RESEARCH
卷 50, 期 16, 页码 9580-9595

出版社

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac713

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资金

  1. National Natural Science Foundation of China [32030064, 91940303, 31730110, 31570823, 31661143031, 31971367]
  2. National Key Research and Development Program of China [2018YFA0107602, 2021YFA1300503]
  3. Strategic Priority Research Program of Chinese Academy of Sciences [XDB38040100]
  4. StarryNight Science Fund at Shanghai Institute for Advanced Study of Zhejiang University [SN-ZJU-SIAS-009]
  5. Science and Technology Commission of Shanghai Municipality [17JC1404900, 18XD1404400]
  6. National Postdoctoral Program for Innovative Talents [BX20180336]
  7. Shanghai Super Postdoctoral Program
  8. CAS Pioneer Hundred Talents program (type A)

向作者/读者索取更多资源

This study reports a new RNA editing system that allows precise gene editing using a single engineered protein, without the need for auxiliary RNA. The system achieves high editing efficiency and low off-target effects, making it applicable for correcting disease-associated gene mutations.
Programmable RNA editing enables rewriting gene expression without changing genome sequences. Current tools for specific RNA editing dependent on the assembly of guide RNA into an RNA/protein complex, causing delivery barrier and low editing efficiency. We report a new gRNA-free system, RNA editing with individual RNA-binding enzyme (REWIRE), to perform precise base editing with a single engineered protein. This artificial enzyme contains a human-originated programmable PUF domain to specifically recognize RNAs and different deaminase domains to achieve efficient A-to-I or C-to-U editing, which achieved 60-80% editing rate in human cells, with a few non-specific editing sites in the targeted region and a low level off-target effect globally. The RNA-binding domain in REWIREs was further optimized to improve editing efficiency and minimize off-target effects. We applied the REWIREs to correct disease-associated mutations and achieve both types of base editing in mice. As a single-component system originated from human proteins, REWIRE presents a precise and efficient RNA editing platform with broad applicability.

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