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Demethylation of Non-CpG Sites in DNA Is Initiated by TET2 5-Methylcytosine Dioxygenase

1
Division of Pharmacology & Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64112, USA
2
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Benoît Miotto
Received: 21 May 2021 / Revised: 9 July 2021 / Accepted: 6 September 2021 / Published: 21 September 2021
In the mammalian genome, cytosine methylation predominantly occurs at CpG sites. In addition, a number of recent studies have uncovered extensive C5 cytosine methylation (5mC) at non-CpG (5mCpH, where H = A/C/T) sites. Little is known about the enzyme responsible for active demethylation of 5mCpH sites. Using a very sensitive and quantitative LC–MS/MS method, we demonstrate that the human TET2, an iron (II)- and 2OG-dependent dioxygenase, which is a frequently mutated gene in several myeloid malignancies, as well as in a number of other types of cancers, can oxidize 5mCpH sites in double-stranded DNA in vitro. Similar to oxidation of 5mCpG, oxidation of 5mC at CpH sites produces 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC) bases in DNA. After 5mCpG, which is the most preferred substrate, TET2 prefers 5mCpC as a substrate, followed by 5mCpA and then 5mCpT. Since the TDG/BER pathway and deformylation or decarboxylation of 5fC or 5caC, respectively, can convert 5fCpH and 5caCpH to an unmodified cytosine base in DNA, our results suggest a novel demethylation pathway of 5mCpH sites initiated by TET2 dioxygenase. View Full-Text
Keywords: epigenetics; DNA demethylation; TET dioxygenases; substrate specificity; 5-methylcytosine oxidation; non-CpG demethylation epigenetics; DNA demethylation; TET dioxygenases; substrate specificity; 5-methylcytosine oxidation; non-CpG demethylation
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MDPI and ACS Style

Dey, A.S.; Bhattacharya, C.; Guan, Y.; Jha, B.K.; Mukherji, M. Demethylation of Non-CpG Sites in DNA Is Initiated by TET2 5-Methylcytosine Dioxygenase. DNA 2021, 1, 26-36. https://0-doi-org.brum.beds.ac.uk/10.3390/dna1010004

AMA Style

Dey AS, Bhattacharya C, Guan Y, Jha BK, Mukherji M. Demethylation of Non-CpG Sites in DNA Is Initiated by TET2 5-Methylcytosine Dioxygenase. DNA. 2021; 1(1):26-36. https://0-doi-org.brum.beds.ac.uk/10.3390/dna1010004

Chicago/Turabian Style

Dey, Aninda S., Chayan Bhattacharya, Yihong Guan, Babal K. Jha, and Mridul Mukherji. 2021. "Demethylation of Non-CpG Sites in DNA Is Initiated by TET2 5-Methylcytosine Dioxygenase" DNA 1, no. 1: 26-36. https://0-doi-org.brum.beds.ac.uk/10.3390/dna1010004

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