JOM KITA KE POLITEKNIK

A two-residue nascent strand steric gate controls synthesis of 2'-O-methyl- and 2'-O-(2-methoxyethyl)-RNA (Record no. 2212)

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Personal name Freund, Niklas
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9 (RLIN) 2248
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Title A two-residue nascent strand steric gate controls synthesis of 2'-O-methyl- and 2'-O-(2-methoxyethyl)-RNA
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Date of publication, distribution, etc. 2022-10-13.
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General note /pmc/articles/PMC7614059/
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General note /pubmed/36229679
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Summary, etc. Steric exclusion is a key element of enzyme substrate specificity, including in polymerases. Such substrate specificity restricts the enzymatic synthesis of 2'-modified nucleic acids, which are of interest in nucleic acid-based drug development. Here we describe the discovery of a two-residue, nascent strand, steric control "gate" in an archaeal DNA polymerase. We show that engineering of the gate to reduce steric bulk in the context of a previously-described RNA polymerase activity unlocks the synthesis of 2'-modified RNA oligomers, specifically the efficient synthesis of both defined and random-sequence 2'-O-methyl-RNA (2'OMe-RNA) and 2'-O-(2-methoxyethyl)-RNA (MOE-RNA) oligomers up to 750 nt. This enabled the discovery of RNA endonuclease catalysts entirely composed of 2'OMe-RNA ("2'OMezymes") for the allele-specific cleavage of oncogenic KRAS (G12D) and β-catenin CTNNB1 (S33Y) mRNAs, and the elaboration of mixed 2'OMe- / MOE-RNA aptamers with high affinity for Vascular Endothelial Growth Factor. Our results open up these 2'-modified RNAs-used in several approved nucleic acid therapeutics-for enzymatic synthesis and a wider exploration in directed evolution and nanotechnology.
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Language note en
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Topical term or geographic name as entry element Article
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Personal name Taylor, Alexander I.
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9 (RLIN) 1456
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Personal name Arangundy-Franklin, Sebastian
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9 (RLIN) 2249
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Personal name Subramanian, Nithya
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9 (RLIN) 2250
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Personal name Peak-Che
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9 (RLIN) 1459
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Personal name Whitaker, Amy M.
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9 (RLIN) 2251
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Personal name Freudenthal, Bret D.
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9 (RLIN) 2252
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Personal name Abramov, Mikhail
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9 (RLIN) 2253
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Herdewijn, Piet
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9 (RLIN) 2254
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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/s41557-022-01050-8">http://dx.doi.org/10.1038/s41557-022-01050-8</a>
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