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Nucleobase Modifiers Identify TET Enzymes as Bifunctional DNA Dioxygenases Capable of Direct N‐Demethylation
Author(s) -
Ghanty Uday,
Wang Tong,
Kohli Rahul M.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202002751
Subject(s) - nucleobase , cytosine , demethylase , 5 hydroxymethylcytosine , enzyme , demethylation , dna , 5 methylcytosine , dna demethylation , chemistry , biochemistry , dna methylation , stereochemistry , biology , gene , gene expression , histone
Abstract TET family enzymes are known for oxidation of the 5‐methyl substituent on 5‐methylcytosine (5mC) in DNA. 5mC oxidation generates the stable base 5‐hydroxymethylcytosine (5hmC), starting an indirect, multi‐step process that ends with reversion of 5mC to unmodified cytosine. While probing the nucleobase determinants of 5mC recognition, we discovered that TET enzymes are also proficient as direct N‐demethylases of cytosine bases. We find that N‐demethylase activity can be readily observed on substrates lacking a 5‐methyl group and, remarkably, TET enzymes can be similarly proficient in either oxidation of 5mC or demethylation of N4‐methyl substituents. Our results indicate that TET enzymes can act as both direct and indirect demethylases, highlight the active‐site plasticity of these Fe II /α‐ketoglutarate‐dependent dioxygenases, and suggest activity on unexplored substrates that could reveal new TET biology.