Cytosine methylation (WP3585)

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).
last edited

Authors

Fehrhart, Susan, Mkutmon, and MaintBot

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: regulatory pathway

Participants

Label Type Compact Identifier
5-methylcytosine Metabolite hmdb:HMDB0002894
MECP2 Protein uniprot:P51608
ethanol Metabolite chebi:16236
MBD3 Protein uniprot:O95983
a-ketoglutarate Metabolite chebi:16810
isocitrate Metabolite chebi:36453
hsa-mir-29a Rna mirbase.mature:MIMAT0000086
5-carboxylcytosine Metabolite chebi:76793
IDH1 Protein uniprot:O75874
TET2 Protein uniprot:Q6N021
DNMT1 Protein uniprot:P26358
TET3 Protein uniprot:K9JJH7
TET1 Protein uniprot:Q8NFU7
TDG Protein uniprot:Q13569
base excision repair Pathway wikipathways:WP3399
2-hydroxyglutarate Metabolite chebi:11596
5-formylcytosine Metabolite chebi:76794
5-hydroxymethylcytosine Metabolite chebi:76792
cytosine Metabolite chebi:16040
IDH2 Protein uniprot:P48735

References

  1. Wang J, Tang J, Lai M, Zhang H. 5-Hydroxymethylcytosine and disease. Mutat Res Rev Mutat Res. 2014;762:167–75. PubMed Europe PMC Scholia