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N6mdAChemRXiV.pdf (17.34 MB)

Selective Chemical Functionalization at N6 mdA Residues in DNA

preprint
submitted on 21.09.2020 and posted on 22.09.2020 by Manuel Nappi, Alexander Hofer, Shankar Balasubramanian, Matthew Gaunt
Selective chemistry that modifies the structure of DNA and RNA is essential to understanding the role of epigenetic modifications. We report a visible-light-activated photocatalytic process that introduces a covalent modification at a C(sp3 )–H bond in the methyl group of N6-methyl-adenosine–an epigenetic modification of emerging importance. A carefully orchestrated reaction combines reduction of a nitropyridine to form a nitrosopyridine spin-trapping reagent and an exquisitely selective tertiary aminemediated hydrogen-atom abstraction at the N6-methyl group to form an a-amino radical. Cross-coupling of the putative a-amino radical with nitrosopyridine leads to a stable conjugate, installing a label at N6- methyl-adenosine. We show that N6-methyl-adenosine-containing oligonucleotides can be enriched from complex mixtures, paving the way for applications to identify this modification in genomic DNA and RNA

Funding

Marie Curie Foundation (H2020-MSCA-IF-2017, ID: 789407 and H2020-MSCA-IF-2015, ID: 702462

Swiss National Science Foundation (P2ZHP2_168448)

Leverhulme Trust (RPG-2016-370)

EPSRC (EP/N031792/1)

Wellcome Trust (209441/z/17/z)

Cancer Research UK programme grant (C9681/A18618) and core funding (C14303/A17197)

Royal Society (for Wolfson Merit Award)

History

Email Address of Submitting Author

mjg32@cam.ac.uk

Institution

University of Cambridge, Department of Chemistry

Country

United Kingdom

ORCID For Submitting Author

0000-0002-7214-608X

Declaration of Conflict of Interest

SB is an advisor and shareholder of Cambridge Epigenetix Ltd. A patent application is pending. GB Patent Application No: 2014404.4

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