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  • Title: Nucleobase Modifiers Identify TET Enzymes as Bifunctional DNA Dioxygenases Capable of Direct N-Demethylation.
    Author: Ghanty U, Wang T, Kohli RM.
    Journal: Angew Chem Int Ed Engl; 2020 Jul 06; 59(28):11312-11315. PubMed ID: 32271979.
    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 FeII /α-ketoglutarate-dependent dioxygenases, and suggest activity on unexplored substrates that could reveal new TET biology.
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