Biochemical reconstitution of TET1–TDG–BER-dependent active DNA demethylation reveals a highly coordinated mechanism

Alain R. Weber, Claudia Krawczyk, Adam B. Robertson, Anna Kuśnierczyk, Cathrine B. Vågbø, David Schuermann, Arne Klungland and Primo Schär ()
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Alain R. Weber: University of Basel, Mattenstrasse 28, Basel CH-4058, Switzerland
Claudia Krawczyk: University of Basel, Mattenstrasse 28, Basel CH-4058, Switzerland
Adam B. Robertson: Oslo University Hospital
Anna Kuśnierczyk: Proteomics and Metabolomics Core Facility, PROMEC, Norwegian University of Science and Technology
Cathrine B. Vågbø: Proteomics and Metabolomics Core Facility, PROMEC, Norwegian University of Science and Technology
David Schuermann: University of Basel, Mattenstrasse 28, Basel CH-4058, Switzerland
Arne Klungland: Oslo University Hospital
Primo Schär: University of Basel, Mattenstrasse 28, Basel CH-4058, Switzerland

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Cytosine methylation in CpG dinucleotides is an epigenetic DNA modification dynamically established and maintained by DNA methyltransferases and demethylases. Molecular mechanisms of active DNA demethylation began to surface only recently with the discovery of the 5-methylcytosine (5mC)-directed hydroxylase and base excision activities of ten–eleven translocation (TET) proteins and thymine DNA glycosylase (TDG). This implicated a pathway operating through oxidation of 5mC by TET proteins, which generates substrates for TDG-dependent base excision repair (BER) that then replaces 5mC with C. Yet, direct evidence for a productive coupling of TET with BER has never been presented. Here we show that TET1 and TDG physically interact to oxidize and excise 5mC, and proof by biochemical reconstitution that the TET–TDG–BER system is capable of productive DNA demethylation. We show that the mechanism assures a sequential demethylation of symmetrically methylated CpGs, thereby avoiding DNA double-strand break formation but contributing to the mutability of methylated CpGs.

Date: 2016
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DOI: 10.1038/ncomms10806

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