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J Am Chem Soc. 2017 Dec 6;139(48):17213-17216. doi: 10.1021/jacs.7b06837. Epub 2017 Nov 15.

N6-Allyladenosine: A New Small Molecule for RNA Labeling Identified by Mutation Assay.

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MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University , Zheda Road 38, Hangzhou 310027, China.
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago , Chicago, Illinois 60637, United States.
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center , New York, New York 10065, United States.
Life Sciences Institute, Zhejiang University , Yuhangtang Road 866, Hangzhou 310058, China.


RNA labeling is crucial for the study of RNA structure and metabolism. Herein we report N6-allyladenosine (a6A) as a new small molecule for RNA labeling through both metabolic and enzyme-assisted manners. a6A behaves like A and can be metabolically incorporated into newly synthesized RNAs inside mammalian cells. We also show that human RNA N6-methyladenosine (m6A) methyltransferases METTL3/METTL14 can work with a synthetic cofactor, namely allyl-SAM (S-adenosyl methionine with methyl replaced by allyl) in order to site-specifically install an allyl group to the N6-position of A within specific sequence to generate a6A-labeled RNAs. The iodination of N6-allyl group of a6A under mild buffer conditions spontaneously induces the formation of N1,N6-cyclized adenosine and creates mutations at its opposite site during complementary DNA synthesis of reverse transcription. The existing m6A in RNA is inert to methyltransferase-assisted allyl labeling, which offers a chance to differentiate m6A from A at individual RNA sites. Our work demonstrates a new method for RNA labeling, which could find applications in developing sequencing methods for nascent RNAs and RNA modifications.

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