Enhanced control of RNA modification and CRISPR-Cas activity through redox-triggered disulfide cleavage.

Autor: Lei H; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China., Xiong W; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China., Li M; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China., Qi Q; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China., Liu X; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China., Wang S; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China., Tian T; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China. Electronic address: ttian@whu.edu.cn., Zhou X; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, The Institute of Molecular Medicine, Wuhan University People's Hospital, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430072, Hubei, China.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Oct 01; Vol. 112, pp. 117878. Date of Electronic Publication: 2024 Aug 16.
DOI: 10.1016/j.bmc.2024.117878
Abstrakt: Chemical RNA modification has emerged as a flexible approach for post-synthetic modifications in chemical biology research. Guide RNA (gRNA) plays a crucial role in the clustered regularly interspaced short palindromic repeats and associated protein system (CRISPR-Cas). Several toolkits have been developed to regulate gene expression and editing through modifications of gRNA. However, conditional regulation strategies to control gene editing in cells as required are still lacking. In this context, we introduce a strategy employing a cyclic disulfide-substituted acylating agent to randomly acylate the 2'-OH group on the gRNA strand. The CRISPR-Cas systems demonstrate off-on transformation activity driven by redox-triggered disulfide cleavage and undergo intramolecular cyclization, which releases the functionalized gRNA. Dithiothreitol (DTT) exhibits superior reductive capabilities in cleaving disulfides compared to glutathione (GSH), requiring fewer reductants. This acylation method with cyclic disulfides enables conditional control of CRISPR-Cas9, CRISPR-Cas13a, RNA hybridization, and aptamer folding. Our strategy facilitates precise in vivo control of gene editing, making it particularly valuable for targeted applications.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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