Autocatalytic base editing for RNA-responsive translational control.
| Authors | |
| Abstract | Genetic circuits that control transgene expression in response to pre-defined transcriptional cues would enable the development of smart therapeutics. To this end, here we engineer programmable single-transcript RNA sensors in which adenosine deaminases acting on RNA (ADARs) autocatalytically convert target hybridization into a translational output. Dubbed DART VADAR (Detection and Amplification of RNA Triggers via ADAR), our system amplifies the signal from editing by endogenous ADAR through a positive feedback loop. Amplification is mediated by the expression of a hyperactive, minimal ADAR variant and its recruitment to the edit site via an orthogonal RNA targeting mechanism. This topology confers high dynamic range, low background, minimal off-target effects, and a small genetic footprint. We leverage DART VADAR to detect single nucleotide polymorphisms and modulate translation in response to endogenous transcript levels in mammalian cells. |
| Year of Publication | 2023
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| Journal | Nature communications
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| Volume | 14
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| Issue | 1
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| Pages | 1339
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| Date Published | 03/2023
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| ISSN | 2041-1723
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| DOI | 10.1038/s41467-023-36851-z
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| PubMed ID | 36906659
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