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A modular XNAzyme cleaves long, structured RNAs under physiological conditions and enables allele-specific gene silencing (Record no. 1808)

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Personal name Taylor, Alexander I.
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9 (RLIN) 1456
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Title A modular XNAzyme cleaves long, structured RNAs under physiological conditions and enables allele-specific gene silencing
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Date of publication, distribution, etc. 2022-11.
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General note /pmc/articles/PMC7613789/
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General note /pubmed/36064973
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Summary, etc. Nucleic acid catalysts (ribozymes, DNA- and XNAzymes) cleave target (m)RNAs with high specificity but have shown limited efficacy in clinical application. Here we report on the in vitro evolution and engineering of a highly specific modular RNA endonuclease XNAzyme, FR6_1, composed of 2'-deoxy-2'-fluoro-β-D-arabino nucleic acid (FANA). FR6_1 overcomes activity limitations of previous DNA- and XNAzymes and can be retargeted to cleave highly structured full-length (>5 kb) BRAF and KRAS mRNAs at physiological Mg(2+) concentrations with allelic selectivity for tumour-associated (BRAF V600E and KRAS G12D) mutations. Phosphorothioate-FANA modification enhances FR6_1 biostability and enables rapid KRAS mRNA knockdown in cultured human adenocarcinoma cells with a G12D-allele-specific component provided by in vivo XNAzyme cleavage activity. These results provide a starting point for the development of improved gene silencing agents based on FANA or other XNA chemistries.
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Terms governing use and reproduction
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Terms governing use and reproduction https://www.springernature.com/gp/open-research/policies/accepted-manuscript-termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms
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Language note en
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Topical term or geographic name as entry element Article
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Genre/form data or focus term Text
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Personal name Wan, Christopher J.K.
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9 (RLIN) 1457
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Personal name Donde, Maria J.
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9 (RLIN) 1458
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Personal name Peak-Che
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9 (RLIN) 1459
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Personal name Holliger, Philipp
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9 (RLIN) 1460
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Note Nat Chem
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Uniform Resource Identifier <a href="http://dx.doi.org/10.1038/s41557-022-01021-z">http://dx.doi.org/10.1038/s41557-022-01021-z</a>
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