Programmable mammalian translational modulators by CRISPR-associated proteins

Shunsuke Kawasaki (), Hiroki Ono, Moe Hirosawa, Takeru Kuwabara, Shunsuke Sumi, Suji Lee, Knut Woltjen and Hirohide Saito ()
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Shunsuke Kawasaki: Kyoto University
Hiroki Ono: Kyoto University
Moe Hirosawa: Kyoto University
Takeru Kuwabara: Kyoto University
Shunsuke Sumi: Kyoto University
Suji Lee: Kyoto University
Knut Woltjen: Kyoto University
Hirohide Saito: Kyoto University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Translational modulation based on RNA-binding proteins can be used to construct artificial gene circuits, but RNA-binding proteins capable of regulating translation efficiently and orthogonally remain scarce. Here we report CARTRIDGE (Cas-Responsive Translational Regulation Integratable into Diverse Gene control) to repurpose Cas proteins as translational modulators in mammalian cells. We demonstrate that a set of Cas proteins efficiently and orthogonally repress or activate the translation of designed mRNAs that contain a Cas-binding RNA motif in the 5’-UTR. By linking multiple Cas-mediated translational modulators, we designed and built artificial circuits like logic gates, cascades, and half-subtractor circuits. Moreover, we show that various CRISPR-related technologies like anti-CRISPR and split-Cas9 platforms could be similarly repurposed to control translation. Coupling Cas-mediated translational and transcriptional regulation enhanced the complexity of synthetic circuits built by only introducing a few additional elements. Collectively, CARTRIDGE has enormous potential as a versatile molecular toolkit for mammalian synthetic biology.

Date: 2023
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DOI: 10.1038/s41467-023-37540-7

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