TET Enzymes, TDG and the Dynamics of DNA Demethylation

Overview

Journal Nature

Specialty Science

Date 2013 Oct 25

PMID 24153300

Citations 757

Authors

Rahul M Kohli

Yi Zhang

Affiliations

Soon will be listed here.

Abstract

DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.

Citing Articles

Pulmonary Hypertension: Molecular Mechanisms and Clinical Studies.

Adu-Amankwaah J, You Q, Liu X, Jiang J, Yang D, Liu K MedComm (2020). 2025; 6(3):e70134.

PMID: 40066229 PMC: 11892029. DOI: 10.1002/mco2.70134.

The epigenetic hallmarks of immune cells in cancer.

Ji Y, Xiao C, Fan T, Deng Z, Wang D, Cai W Mol Cancer. 2025; 24(1):66.

PMID: 40038722 PMC: 11881328. DOI: 10.1186/s12943-025-02255-4.

Landscape analysis of m6A modification reveals the dysfunction of bone metabolism in osteoporosis mice.

Zheng L, Lan C, Gao X, Zhu A, Chen Y, Lin J Heliyon. 2025; 11(3):e42123.

PMID: 39991256 PMC: 11847259. DOI: 10.1016/j.heliyon.2025.e42123.

Active DNA demethylation is upstream of rod-photoreceptor fate determination and required for retinal development.

Hernandez-Nunez I, Urman A, Zhang X, Jacobs W, Hoffman C, Rebba S bioRxiv. 2025; .

PMID: 39975078 PMC: 11838574. DOI: 10.1101/2025.02.03.636318.

Mechanism analysis and targeted therapy of IDH gene mutation in glioma.

Ma X, Sun C, Ding X, Xu J, Zhang Y, Deng T Am J Cancer Res. 2025; 15(1):248-270.

PMID: 39949933 PMC: 11815359. DOI: 10.62347/NSXC2205.

References

Gu T, Guo F, Yang H, Wu H, Xu G, Liu W . The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011; 477(7366):606-10. DOI: 10.1038/nature10443. View

Iyer L, Tahiliani M, Rao A, Aravind L . Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle. 2009; 8(11):1698-710. PMC: 2995806. DOI: 10.4161/cc.8.11.8580. View

Losman J, Looper R, Koivunen P, Lee S, Schneider R, McMahon C . (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013; 339(6127):1621-5. PMC: 3836459. DOI: 10.1126/science.1231677. View

Zhang H, Zhang X, Clark E, Mulcahey M, Huang S, Shi Y . TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. Cell Res. 2010; 20(12):1390-3. DOI: 10.1038/cr.2010.156. View

Kumar R, DiMenna L, Schrode N, Liu T, Franck P, Munoz-Descalzo S . AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes. Nature. 2013; 500(7460):89-92. PMC: 3762466. DOI: 10.1038/nature12299. View

Maiti A, Drohat A . Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem. 2011; 286(41):35334-35338. PMC: 3195571. DOI: 10.1074/jbc.C111.284620. View

Baylin S, Jones P . A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011; 11(10):726-34. PMC: 3307543. DOI: 10.1038/nrc3130. View

Smith Z, Chan M, Mikkelsen T, Gu H, Gnirke A, Regev A . A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012; 484(7394):339-44. PMC: 3331945. DOI: 10.1038/nature10960. View

Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N . MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell. 2012; 151(7):1417-30. PMC: 3653293. DOI: 10.1016/j.cell.2012.11.022. View

10.

Barreto G, Schafer A, Marhold J, Stach D, Swaminathan S, Handa V . Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007; 445(7128):671-5. DOI: 10.1038/nature05515. View

11.

Cortazar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E . Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature. 2011; 470(7334):419-23. DOI: 10.1038/nature09672. View

12.

PENN N, SUWALSKI R, ORiley C, Bojanowski K, YURA R . The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid. Biochem J. 1972; 126(4):781-90. PMC: 1178489. DOI: 10.1042/bj1260781. View

13.

Kriaucionis S, Heintz N . The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009; 324(5929):929-30. PMC: 3263819. DOI: 10.1126/science.1169786. View

14.

Thillainadesan G, Chitilian J, Isovic M, Ablack J, Mymryk J, Tini M . TGF-β-dependent active demethylation and expression of the p15ink4b tumor suppressor are impaired by the ZNF217/CoREST complex. Mol Cell. 2012; 46(5):636-49. DOI: 10.1016/j.molcel.2012.03.027. View

15.

Smiley J, Kundracik M, Landfried D, Barnes Sr V, Axhemi A . Genes of the thymidine salvage pathway: thymine-7-hydroxylase from a Rhodotorula glutinis cDNA library and iso-orotate decarboxylase from Neurospora crassa. Biochim Biophys Acta. 2005; 1723(1-3):256-64. DOI: 10.1016/j.bbagen.2005.02.001. View

16.

Costa Y, Ding J, Theunissen T, Faiola F, Hore T, Shliaha P . NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature. 2013; 495(7441):370-4. PMC: 3606645. DOI: 10.1038/nature11925. View

17.

Wu H, DAlessio A, Ito S, Xia K, Wang Z, Cui K . Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature. 2011; 473(7347):389-93. PMC: 3539771. DOI: 10.1038/nature09934. View

18.

Xu Y, Xu C, Kato A, Tempel W, Abreu J, Bian C . Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell. 2012; 151(6):1200-13. PMC: 3705565. DOI: 10.1016/j.cell.2012.11.014. View

19.

Rangam G, Schmitz K, Cobb A, Petersen-Mahrt S . AID enzymatic activity is inversely proportional to the size of cytosine C5 orbital cloud. PLoS One. 2012; 7(8):e43279. PMC: 3423351. DOI: 10.1371/journal.pone.0043279. View

20.

Gao Y, Chen J, Li K, Wu T, Huang B, Liu W . Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell. 2013; 12(4):453-69. DOI: 10.1016/j.stem.2013.02.005. View