TET1,2,3 and TDG demethylate DNA (Homo sapiens)

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1-3, 5-8, 10...4, 17, 19, 20, 254, 19, 20, 252, 7, 9, 14, 18...12nucleoplasmcytosolO25-caCDNA containing 5-hmCTDG DNA containing 5-mC5-fC2OGDNA containing 5-caCTDG:AP-dsDNACO2CO2CO2VitC2OGTDGSUCCASUCCAH2OO2DNA containing 5-fC2OGSUCCAO2TET1,2,3


Description

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). 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). Source:Reactome.

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Bibliography

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  1. Iqbal K, Jin SG, Pfeifer GP, Szabó PE.; ''Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosine.''; PubMed Europe PMC Scholia
  2. Minor EA, Court BL, Young JI, Wang G.; ''Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine.''; PubMed Europe PMC Scholia
  3. Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews S, Reik W.; ''Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation.''; PubMed Europe PMC Scholia
  4. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J, Laiho A, Tahiliani M, Sommer CA, Mostoslavsky G, Lahesmaa R, Orkin SH, Rodig SJ, Daley GQ, Rao A.; ''Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells.''; PubMed Europe PMC Scholia
  5. Zhang RR, Cui QY, Murai K, Lim YC, Smith ZD, Jin S, Ye P, Rosa L, Lee YK, Wu HP, Liu W, Xu ZM, Yang L, Ding YQ, Tang F, Meissner A, Ding C, Shi Y, Xu GL.; ''Tet1 regulates adult hippocampal neurogenesis and cognition.''; PubMed Europe PMC Scholia
  6. Guo JU, Su Y, Zhong C, Ming GL, Song H.; ''Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain.''; PubMed Europe PMC Scholia
  7. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL.; ''Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA.''; PubMed Europe PMC Scholia
  8. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A.; ''Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.''; PubMed Europe PMC Scholia
  9. Kohli RM, Zhang Y.; ''TET enzymes, TDG and the dynamics of DNA demethylation.''; PubMed Europe PMC Scholia
  10. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A.; ''Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.''; PubMed Europe PMC Scholia
  11. Ponnaluri VK, Maciejewski JP, Mukherji M.; ''A mechanistic overview of TET-mediated 5-methylcytosine oxidation.''; PubMed Europe PMC Scholia
  12. Hu L, Li Z, Cheng J, Rao Q, Gong W, Liu M, Shi YG, Zhu J, Wang P, Xu Y.; ''Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation.''; PubMed Europe PMC Scholia
  13. Franchini DM, Schmitz KM, Petersen-Mahrt SK.; ''5-Methylcytosine DNA demethylation: more than losing a methyl group.''; PubMed Europe PMC Scholia
  14. Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, Luo C, Jiang H, He C.; ''Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA.''; PubMed Europe PMC Scholia
  15. Wu H, D'Alessio AC, Ito S, Xia K, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y.; ''Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells.''; PubMed Europe PMC Scholia
  16. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y.; ''Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.''; PubMed Europe PMC Scholia
  17. Maiti A, Morgan MT, Pozharski E, Drohat AC.; ''Crystal structure of human thymine DNA glycosylase bound to DNA elucidates sequence-specific mismatch recognition.''; PubMed Europe PMC Scholia
  18. Blaschke K, Ebata KT, Karimi MM, Zepeda-Martínez JA, Goyal P, Mahapatra S, Tam A, Laird DJ, Hirst M, Rao A, Lorincz MC, Ramalho-Santos M.; ''Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells.''; PubMed Europe PMC Scholia
  19. Wu H, Zhang Y.; ''Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation.''; PubMed Europe PMC Scholia
  20. Rasmussen KD, Helin K.; ''Role of TET enzymes in DNA methylation, development, and cancer.''; PubMed Europe PMC Scholia
  21. Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, Jui J, Jin SG, Jiang Y, Pfeifer GP, Lu Q.; ''Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis.''; PubMed Europe PMC Scholia
  22. Hashimoto H, Hong S, Bhagwat AS, Zhang X, Cheng X.; ''Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation.''; PubMed Europe PMC Scholia
  23. Maiti A, Drohat AC.; ''Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites.''; PubMed Europe PMC Scholia
  24. Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y.; ''Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification.''; PubMed Europe PMC Scholia
  25. Kaas GA, Zhong C, Eason DE, Ross DL, Vachhani RV, Ming GL, King JR, Song H, Sweatt JD.; ''TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation.''; PubMed Europe PMC Scholia
  26. Cadet J, Wagner JR.; ''TET enzymatic oxidation of 5-methylcytosine, 5-hydroxymethylcytosine and 5-formylcytosine.''; PubMed Europe PMC Scholia
  27. Kinney SR, Pradhan S.; ''Ten eleven translocation enzymes and 5-hydroxymethylation in mammalian development and cancer.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114686view16:16, 25 January 2021ReactomeTeamReactome version 75
113132view11:19, 2 November 2020ReactomeTeamReactome version 74
112364view15:29, 9 October 2020ReactomeTeamReactome version 73
101265view11:15, 1 November 2018ReactomeTeamreactome version 66
100803view20:43, 31 October 2018ReactomeTeamreactome version 65
100345view19:21, 31 October 2018ReactomeTeamreactome version 64
99890view16:03, 31 October 2018ReactomeTeamreactome version 63
99447view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99114view12:40, 31 October 2018ReactomeTeamreactome version 62
93986view13:49, 16 August 2017ReactomeTeamreactome version 61
93590view11:28, 9 August 2017ReactomeTeamreactome version 61
88406view11:42, 5 August 2016FehrhartOntology Term : 'DNA modification pathway' added !
86698view09:24, 11 July 2016ReactomeTeamreactome version 56
83167view10:15, 18 November 2015ReactomeTeamVersion54
81534view13:04, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:30915 (ChEBI)
5-caCMetaboliteCHEBI:76793 (ChEBI)
5-fCMetaboliteCHEBI:76794 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
DNA containing 5-caCR-NUL-5220996 (Reactome)
DNA containing 5-fCR-NUL-5221062 (Reactome)
DNA containing 5-hmCR-NUL-5221008 (Reactome)
DNA containing 5-mCR-NUL-212172 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
SUCCAMetaboliteCHEBI:15741 (ChEBI)
TDG ProteinQ13569 (Uniprot-TrEMBL)
TDG:AP-dsDNAComplexR-HSA-110191 (Reactome)
TDGProteinQ13569 (Uniprot-TrEMBL)
TET1,2,3R-HSA-5220974 (Reactome)
VitCMetaboliteCHEBI:29073 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2OGR-HSA-5220952 (Reactome)
2OGR-HSA-5220990 (Reactome)
2OGR-HSA-5221014 (Reactome)
5-caCArrowR-HSA-5221061 (Reactome)
5-fCArrowR-HSA-5220959 (Reactome)
CO2ArrowR-HSA-5220952 (Reactome)
CO2ArrowR-HSA-5220990 (Reactome)
CO2ArrowR-HSA-5221014 (Reactome)
DNA containing 5-caCArrowR-HSA-5220952 (Reactome)
DNA containing 5-caCR-HSA-5221061 (Reactome)
DNA containing 5-fCArrowR-HSA-5220990 (Reactome)
DNA containing 5-fCR-HSA-5220952 (Reactome)
DNA containing 5-fCR-HSA-5220959 (Reactome)
DNA containing 5-hmCArrowR-HSA-5221014 (Reactome)
DNA containing 5-hmCR-HSA-5220990 (Reactome)
DNA containing 5-mCR-HSA-5221014 (Reactome)
H2OArrowR-HSA-5220990 (Reactome)
O2R-HSA-5220952 (Reactome)
O2R-HSA-5220990 (Reactome)
O2R-HSA-5221014 (Reactome)
R-HSA-5220952 (Reactome) As inferred from mouse, TET1, TET2, and TET3 each oxidize 5-formylcytosine (5-fC) in DNA using molecular oxygen and 2-oxoglutarate to yield 5-carboxylcytosine (5-caC).
R-HSA-5220959 (Reactome) Thymine DNA glycosylase (TDG) excises 5-formylcytosine (5-fC) from DNA (Maiti and Drohat 2011, Zhang et al. 2012, inferred from mouse in He et al. 2011) by flipping the base out of the helix and cleaving the N-glycosidic bond to leave an abasic site (apurinic/apyrimidinic site, AP site). TDG interacts with the G opposite the excised base and remains bound to the abasic site (Maiti et al 2008). Dissociation of TDG from DNA is the rate-limiting step of the reaction.
R-HSA-5220990 (Reactome) As inferred from mouse, TET1, TET2, and TET3 oxidize 5-hydroxymethylcytosine (5-hmC) in DNA using molecular oxygen and 2-oxoglutarate to yield 5-formylcytosine (5-fC), carbon dioxide, and succinate.
R-HSA-5221014 (Reactome) 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).
R-HSA-5221061 (Reactome) Thymine DNA glycosylase (TDG) excises 5-carboxylcytosine (5-caC) from DNA (Maiti and Drohat 2011, Hashimoto et al. 2012, Zhang et al. 2012, inferred from mouse in He et al. 2011) by flipping the base out of the helix and cleaving the N-glycosidic bond to leave an abasic site (apurinic/apyrimidinic site, AP site) (Hashimoto et al. 2012, Zhang et al. 2012). TDG interacts with the G opposite the excised base and remains bound to the abasic site (Maiti et al. 2008). Dissociation of TDG from DNA is the rate-limiting step of the reaction.
SUCCAArrowR-HSA-5220952 (Reactome)
SUCCAArrowR-HSA-5220990 (Reactome)
SUCCAArrowR-HSA-5221014 (Reactome)
TDG:AP-dsDNAArrowR-HSA-5220959 (Reactome)
TDG:AP-dsDNAArrowR-HSA-5221061 (Reactome)
TDGR-HSA-5220959 (Reactome)
TDGR-HSA-5221061 (Reactome)
TDGmim-catalysisR-HSA-5220959 (Reactome)
TDGmim-catalysisR-HSA-5221061 (Reactome)
TET1,2,3mim-catalysisR-HSA-5220952 (Reactome)
TET1,2,3mim-catalysisR-HSA-5220990 (Reactome)
TET1,2,3mim-catalysisR-HSA-5221014 (Reactome)
VitCArrowR-HSA-5221014 (Reactome)
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