Cytosine methylation (Homo sapiens)

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1wildtype IDHCytosolmutantconversioninhibitionInhibits TET action by binding to methylated and hydroxymethylated cytosinebindingLEGENDcatalysisTET1TET3ethanol5-carboxylcytosineDNMT1hsa-mir-29a5-methylcytosineMBD3a-ketoglutaratebase excision repair5-formylcytosineisocitrateTET2TDGMECP2IDH12-hydroxyglutarate5-hydroxymethylcytosinecytosineIDH2Nucleus


Description

DNA, namely cytosine, methylation is the key event in epigentics. The degree of methylation influences gene expression and methylation disorders are known to be major causes of some diseases like Rett syndrome and some cancer types. Epigenetic effects also contribute to the development of Alzheimers' disease, developmental retardation by alcohol, Huntington's disease and ischemia-reperfusion injury. Methylation is not a static event but a highly dynamic and therefore highly regulated procedure. Cytosine is methylated by DNA methyltransferases (DNMTs) forming 5-methylcytosine (5mC). In a second step, 5mC is transformed to 5-hydroxymethylcytosine (5hmC) by ten-eleven-translocation enzymes (TET1-3). These enzymes are sensitive to regulation by a variety of metabolites (ethanol, a-ketoglutarate, 2-hydroxyglutarate), miRNA and MeCP2 (targeting directly TET1). Proteins binding methylated DNA like MeCP2 or Mbd3 (as part of the NURD complex) also inhibit the conversion by blocking the target. MeCP2 also binds on 5hmC and block the transition to 5-formylcytosine (5fC) which is also catalyzed by the TET enzymes. The conversion back to cytosine is done by tymine DNA glycosylase (TGD) and base excision repair mechanism either directly or over another TET catalyzed step forming 5-carboxylcytosine (5caC).

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Bibliography

  1. Wang J, Tang J, Lai M, Zhang H; ''5-Hydroxymethylcytosine and disease.''; Mutat Res Rev Mutat Res, 2014 PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
106742view13:22, 17 September 2019MaintBotHMDB identifier normalization
94750view15:27, 5 October 2017Mkutmonfix unconnected lines
88828view12:18, 15 August 2016Fehrhartconverted elements of legend to graphical items
87217view14:25, 19 July 2016SusanOntology Term : 'regulatory pathway' added !
85533view07:47, 27 May 2016FehrhartAdded cellular compartments
84793view15:12, 22 March 2016FehrhartRemodelling finished (unconnected lines are in the legend)
84788view15:57, 21 March 2016Fehrhartintermediate save while remodelling
84784view12:31, 21 March 2016FehrhartRestructuring pathway - intermediate save
83745view15:39, 3 December 2015FehrhartModified description
83740view12:24, 3 December 2015FehrhartNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2-hydroxyglutarateMetaboliteCHEBI:11596 (ChEBI)
5-carboxylcytosineMetaboliteCHEBI:76793 (ChEBI)
5-formylcytosineMetaboliteCHEBI:76794 (ChEBI)
5-hydroxymethylcytosineMetaboliteCHEBI:76792 (ChEBI)
5-methylcytosineMetaboliteHMDB0002894 (HMDB)
DNMT1ProteinP26358 (Uniprot-TrEMBL)
IDH1ProteinO75874 (Uniprot-TrEMBL)
IDH2ProteinP48735 (Uniprot-TrEMBL)
MBD3ProteinO95983 (Uniprot-TrEMBL) as part of the NuRD complex
MECP2ProteinP51608 (Uniprot-TrEMBL)
TDGProteinQ13569 (Uniprot-TrEMBL)
TET1ProteinQ8NFU7 (Uniprot-TrEMBL)
TET2ProteinQ6N021 (Uniprot-TrEMBL)
TET3ProteinK9JJH7 (Uniprot-TrEMBL)
a-ketoglutarateMetaboliteCHEBI:16810 (ChEBI) synonym oxoglutarate
base excision repairPathwayWP3399 (WikiPathways)
cytosineMetaboliteCHEBI:16040 (ChEBI)
ethanolMetaboliteCHEBI:16236 (ChEBI)
hsa-mir-29aRnaMIMAT0000086 (miRBase mature sequence)
isocitrateMetaboliteCHEBI:36453 (ChEBI)

Annotated Interactions

No annotated interactions

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