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

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="TET1,2,3 and TDG demethylate DNA" Data-Source="Reactome - http://www.reactome.org" Version="53" Author="May, Bruce" Maintainer="May, Bruce" Organism="Homo sapiens"> <Comment Source="WikiPathways-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.&lt;br&gt;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.&lt;br&gt;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). 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(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). 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</Graphics> <Xref Database="Reactome" ID="R-HSA-5220990" /> </Interaction> <Interaction GraphId="ea768"> <Comment Source="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).</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="416.0" Y="705.0" /> <Point X="416.0" Y="779.0" /> <Anchor Position="0.0" Shape="None" GraphId="ebd23" /> <Anchor Position="0.99" Shape="None" GraphId="c5c03" /> <Anchor Position="0.5" Shape="None" GraphId="caf12" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5220952" /> </Interaction> <Interaction GraphId="d4c41"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="481.0" Y="569.0" GraphRef="a3e13" RelX="-1.0" RelY="-0.034482758620689655" /> <Point X="416.0" Y="705.0" GraphRef="ebd23" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5220952" /> </Interaction> <Interaction GraphId="d619b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="386.0" Y="687.0" GraphRef="d6c42" RelX="0.9649122807017544" RelY="-0.037037037037037035" /> <Point X="416.0" Y="705.0" GraphRef="ebd23" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5220952" /> </Interaction> <Interaction GraphId="c0a4c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="408.0" Y="674.0" GraphRef="b71fe" RelX="-0.02040816326530612" RelY="1.0" /> <Point X="416.0" Y="705.0" GraphRef="ebd23" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5220952" /> </Interaction> <Interaction GraphId="a516a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="416.0" Y="779.0" GraphRef="c5c03" RelX="0.0" RelY="0.7400000000000091" /> <Point X="473.0" Y="845.0" GraphRef="e04c1" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref 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TDG interacts with the G opposite the excised base and remains bound to the abasic site (Maiti et al 2008). 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xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="c1a"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">19372391</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="f08"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">18587051</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Crystal structure 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xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="b31"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">23548903</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Minor EA, Court BL, Young JI, Wang G.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="ae0"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">21496894</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Guo JU, Su Y, Zhong C, Ming GL, Song H.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="a49"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">22974304</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">5-Methylcytosine DNA demethylation: more than losing a methyl group.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Franchini DM, Schmitz KM, Petersen-Mahrt SK.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="ae4"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">23812591</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="e84"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">21817016</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">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.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="b11"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">23403289</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Dynamics of 5-hydroxymethylcytosine and chromatin marks in Mammalian neurogenesis.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hahn MA, Qiu R, Wu X, Li AX, Zhang H, Wang J, Jui J, Jin SG, Jiang Y, Pfeifer GP, Lu Q.</bp:AUTHORS> </bp:PublicationXref> </Biopax> </Pathway>

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