Autocatalytic base editing for RNA-responsive translational control.
Autocatalytic base editing for RNA-responsive translational control.
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DOI：
10.1038/s41467-023-36851-z
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发表时间：
2023-03-11
影响因子：
16.6
通讯作者：
Collins, James J.
中科院分区：
文献类型：
--
作者：
Gayet, Raphael V.;Ilia, Katherine;Razavi, Shiva;Tippens, Nathaniel D.;Lalwani, Makoto A.;Zhang, Kehan;Chen, Jack X.;Chen, Jonathan C.;Vargas-Asencio, Jose;Collins, James J.
控制转基因表达以响应预定义的转录信号的遗传电路将使智能疗法的开发成为可能。为此，我们设计了可编程的单转录RNA传感器，其中腺苷脱氨酶作用于RNA（ADAR）自催化将靶杂交转化为翻译输出。我们的系统被称为DART V阿达尔（通过阿达尔检测和扩增RNA触发器），通过正反馈回路放大内源性阿达尔编辑的信号。扩增是由高度活跃的最小阿达尔变体的表达及其通过正交RNA靶向机制募集到编辑位点介导的。这种拓扑结构赋予高动态范围、低背景、最小脱靶效应和小遗传足迹。我们利用DART VADAR来检测单核苷酸多态性，并根据哺乳动物细胞中的内源性转录水平调节翻译。控制转基因表达以响应预定义的转录信号的遗传电路将使智能疗法的开发成为可能。在这里，作者设计了可编程RNA传感器DART VADAR，其中ADAR自催化地将靶杂交转化为翻译输出，从而通过正反馈放大内源性阿达尔的编辑，并赋予高动态范围和小的遗传足迹。
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. Genetic circuits that control transgene expression in response to pre-defined transcriptional cues would enable the development of smart therapeutics. Here the authors engineer programmable RNA sensors, DART VADARs, in which ADARs autocatalytically convert target hybridization into a translational output, thus amplifying editing by endogenous ADAR via positive feedback and conferring high dynamic range and a small genetic footprint.
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影响因子：
46.9
作者：
Jiang, Kaiyi;Koob, Jeremy;Abudayyeh, Omar O.
通讯作者：
Abudayyeh, Omar O.
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
irCLASH 揭示了人类 ADAR 识别的 RNA 底物
影响因子：
16.8
作者：
Song, Yulong;Yang, Wenbing;Zhang, Rui
通讯作者：
Zhang, Rui
影响因子：
46.9
作者：
Kaseniit, K. Eerik;Katz, Noa;Gao, Xiaojing J.
通讯作者：
Gao, Xiaojing J.
影响因子：
48
作者：
Katrekar, Dhruva;Chen, Genghao;Mali, Prashant
通讯作者：
Mali, Prashant