TET1,2,3 and TDG demethylate DNA

Stable Identifier
Homo sapiens
Active DNA Demethylation by TET1,2,3, Oxidative demethylation of DNA
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About 2-6% of all cytosine residues and 70-80% of cytosine residues in CG dinucleotides in mammalian cells are methylated at the 5 position of the pyrimidine ring. The cytosine residues are methylated by DNA methyltransferases after DNA replication and can be demethylated by passive dilution during subsequent replication or by active modification of the 5-methylcytosine base. Cytosine demethylation is developmentally regulated: one wave of demethylation occurs in primordial germ cells and one wave occurs by active demethylation in the male pronucleus after fertilization.
Some mechanisms of active demethylation remain controversial, however progressive oxidation of the methyl group of 5-methylcytosine followed by base excision by thymine DNA glycosylase (TDG) has been reproducibly demonstrated in vivo (reviewed in Wu and Zhang 2011, Franchini et al 2012, Cadet and Wagner 2013, Kohli and Zhang 2013, Ponnaluri et al. 2013, Rasmussen and Helin 2016). Ten-eleven translocation proteins TET1, TET2, and TET3 are dioxygenases that first oxidize 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) (Tahiliani et al. 2009, Ito et al. 2010), which is found in significant quantities and specific genomic locations in stem cells and neurons (Kinney and Pradhan 2013). TET proteins can further oxidize 5-hmC to 5-formylcytosine (5-fC) and then 5-carboxylcytosine (5-caC) (He et al. 2011, Ito et al. 2011). G:5-fC and G:5-caC base pairs are recognized by TDG, which excises the 5-fC or 5-caC and leaves an abasic site.
TET1 in mouse is expressed in neurons and its expression depends on neuronal activity (Guo et al. 2011, Kaas et al. 2013, Zhang et al. 2013). TET1 is also found in embryonic stem cells (Ficz et al. 2011, Koh et al. 2011, Wu et al. 2011) and in primordial germ cells of mice, where it plays a role in erasure of imprinting (Yamaguchi et al. 2013). TET3 is expressed in oocytes and zygotes of mice and is required for demethylation in the male pronucleus (Gu et al. 2011, Iqbal et al. 2011). TET2 is the most highly expressed TET family protein in hemopoietic stem cells and appears to act as a tumor suppressor. TET2 is also expressed in embryonic stem cells (Koh et al. 2011).
Literature References
PubMed ID Title Journal Year
21460836 Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation

Andrews, S, Branco, MR, Reik, W, Santos, F, Seisenberger, S, Hore, TA, Krueger, F, Ficz, G, Marques, CJ

Nature 2011
24153300 TET enzymes, TDG and the dynamics of DNA demethylation

Kohli, RM, Zhang, Y

Nature 2013
23727577 A mechanistic overview of TET-mediated 5-methylcytosine oxidation

Ponnaluri, VK, Mukherji, M, Maciejewski, JP

Biochem. Biophys. Res. Commun. 2013
22156206 Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation

Wu, H, Zhang, Y

Genes Dev. 2011
22956496 Ten eleven translocation enzymes and 5-hydroxymethylation in mammalian development and cancer

Pradhan, S, Kinney, SR

Adv. Exp. Med. Biol. 2013
22974304 5-Methylcytosine DNA demethylation: more than losing a methyl group

Franchini, DM, Schmitz, KM, Petersen-Mahrt, SK

Annu. Rev. Genet. 2012
27036965 Role of TET enzymes in DNA methylation, development, and cancer

Helin, K, Rasmussen, KD

Genes Dev. 2016
24050399 TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation

Ming, GL, Ross, DL, Kaas, GA, Song, H, Sweatt, JD, Eason, DE, Vachhani, RV, King, JR, Zhong, C

Neuron 2013
21817016 Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA

Li, BZ, Tang, Q, Sun, Y, Jia, Y, Li, X, Chen, Z, Song, CX, Wang, Y, Li, Z, Liu, P, Zhang, K, Ding, J, Li, L, Dai, Q, Xu, GL, He, C, He, YF

Science 2011
23770080 Tet1 regulates adult hippocampal neurogenesis and cognition

Zhang, RR, Wu, HP, Rosa, L, Ye, P, Smith, ZD, Shi, Y, Meissner, A, Jin, S, Murai, K, Ding, YQ, Xu, ZM, Ding, C, Yang, L, Lee, YK, Tang, F, Lim, YC, Xu, GL, Liu, W, Cui, QY

Cell Stem Cell 2013
21295276 Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells

Koh, KP, Rao, A, Huang, Y, Rodig, SJ, Laiho, A, Lahesmaa, R, Cunniff, K, Orkin, SH, Sommer, CA, Yabuuchi, A, Rao, S, Nardone, J, Mostoslavsky, G, Daley, GQ, Tahiliani, M

Cell Stem Cell 2011
21496894 Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain

Ming, GL, Guo, JU, Song, H, Su, Y, Zhong, C

Cell 2011
21451524 Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells

Sun, YE, Xia, K, Wu, H, Ito, S, Cui, K, D'Alessio, AC, Zhang, Y, Zhao, K, Wang, Z

Nature 2011
21778364 Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine

Shen, L, Ito, S, Dai, Q, Zhang, Y, He, C, Wu, SC, Swenberg, JA, Collins, LB

Science 2011
21321204 Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine

Pfeifer, GP, Szabó, PE, Jin, SG, Iqbal, K

Proc. Natl. Acad. Sci. U.S.A. 2011
24045206 TET enzymatic oxidation of 5-methylcytosine, 5-hydroxymethylcytosine and 5-formylcytosine

Cadet, J, Wagner, JR

Mutat. Res. 2013
19372391 Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1

Brudno, Y, Koh, KP, Rao, A, Bandukwala, H, Aravind, L, Pastor, WA, Agarwal, S, Iyer, LM, Liu, DR, Tahiliani, M, Shen, Y

Science 2009
20639862 Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification

Taranova, OV, Ito, S, D'Alessio, AC, Sowers, LC, Zhang, Y, Hong, K

Nature 2010
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