TET1,2,3 oxidizes 5-methylcytosine to 5-hydroxymethylcytosine

Stable Identifier
R-HSA-5221014
Type
Reaction [transition]
Species
Homo sapiens
Compartment
nucleoplasm
ReviewStatus
5/5
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TET1,2,3 oxidizes 5-methylcytosine to 5-hydroxymethylcytosine
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TET1, TET2, and TET3 each oxidize the 5-methyl group of 5-methylcytosine (5-mC) in DNA using molecular oxygen and 2-oxoglutarate as substrates and Fe(II) as a cofactor to yield 5-hydroxymethylcytosine (5-hmC), carbon dioxide, and succinate (Tahiliani et al. 2009, inferred from mouse in Ito et al. 2010). As inferred from mouse, sodium ascorbate (vitamin C) is required for full activity of these enzymes, presumably to maintain the ferrous state of iron (Fe2+) by acting as a reducing agent (Blaschke et al. 2013, Minor et al., 2013). The crystal structure of TET2 indicates that it binds specifically to 5-mC in CG dinucleotides and flips the base out of the helix into proximity of the catalytic Fe(II) where it is oxidized (Hu et al. 2013). TET3 is expressed in murine oocytes and zygotes and is implicated in demethylation of the male pronucleus after fertilization (Iqbal et al. 2011). As inferred from mouse, TET1 and TET2 appear to participate in differentiation of stem cells. TET1,TET2, and TET3 are involved in establishing the increased level of 5-hmC that is characteristic of adult neurons (Guo et al. 2011, inferred from mouse in Hahn et al. 2013). TET2 is expressed in hematopoietic cells where it appears to act as a tumor suppressor (Ko et al. 2010).
Literature References
PubMed ID Title Journal Year
23548903 Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine

Minor, EA, Wang, G, Court, BL, Young, JI

J. Biol. Chem. 2013
24315485 Crystal Structure of TET2-DNA Complex: Insight into TET-Mediated 5mC Oxidation

Wang, P, Cheng, J, Hu, L, Zhu, J, Shi, YG, Gong, W, Rao, Q, Xu, Y, Li, Z, Liu, M

Cell 2013
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
23403289 Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis

Pfeifer, GP, Qiu, R, Jiang, Y, Zhang, H, Jui, J, Lu, Q, Jin, SG, Wang, J, Wu, X, Li, AX, Hahn, MA

Cell Rep 2013
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
21057493 Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

Koh, KP, Rao, A, Ganetzky, R, Huang, Y, Aravind, L, Ko, M, Liu, XS, Bandukwala, HS, Lamperti, ED, Pape, UJ, An, J, Agarwal, S, Tahiliani, M, Jankowska, AM, Maciejewski, JP

Nature 2010
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
23812591 Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells

Goyal, P, Blaschke, K, Lorincz, MC, Rao, A, Mahapatra, S, Zepeda-Martínez, JA, Tam, A, Hirst, M, Karimi, MM, Ebata, KT, Ramalho-Santos, M, Laird, DJ

Nature 2013
Participants
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Output
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Event Information
Go Biological Process
chromosomal 5-methylcytosine DNA demethylation, oxidation pathway (0141167)
Catalyst Activity

5-methylcytosine dioxygenase activity of TET1,2,3 [nucleoplasm]

Physical Entity
TET1,2,3 [nucleoplasm] (Homo sapiens)
Activity
5-methylcytosine dioxygenase activity (GO:0070579)
This event is regulated
Positively by
Regulator
AscH- [nucleoplasm]
Inferred From
Tet1,2,3 oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (Mus musculus)
Authored
May, B  (2013-12-29)
Reviewed
Mukherji, M  (2014-02-21)
Pfeifer, GP  (2014-01-29)
Created
May, B  (2013-12-30)
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