Title: DNA repair enzymes ALKBH2, ALKBH3, and AlkB oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine in vitro.
Authors: Bian, Ke; Lenz, Stefan A P; Tang, Qi; Chen, Fangyi; Qi, Rui; Jost, Marco; Drennan, Catherine L; Essigmann, John M; Wetmore, Stacey D; Li, Deyu
Published In Nucleic Acids Res, (2019 06 20)
Abstract: 5-Methylcytosine (5mC) in DNA CpG islands is an important epigenetic biomarker for mammalian gene regulation. It is oxidized to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) by the ten-eleven translocation (TET) family enzymes, which are α-ketoglutarate (α-KG)/Fe(II)-dependent dioxygenases. In this work, we demonstrate that the epigenetic marker 5mC is modified to 5hmC, 5fC, and 5caC in vitro by another class of α-KG/Fe(II)-dependent proteins-the DNA repair enzymes in the AlkB family, which include ALKBH2, ALKBH3 in huamn and AlkB in Escherichia coli. Theoretical calculations indicate that these enzymes may bind 5mC in the syn-conformation, placing the methyl group comparable to 3-methylcytosine, the prototypic substrate of AlkB. This is the first demonstration of the AlkB proteins to oxidize a methyl group attached to carbon, instead of nitrogen, on a DNA base. These observations suggest a broader role in epigenetics for these DNA repair proteins.
PubMed ID: 31114894
MeSH Terms: 5-Methylcytosine/analogs & derivatives*; 5-Methylcytosine/metabolism*; AlkB Enzymes/genetics; AlkB Enzymes/metabolism*; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase/genetics; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase/metabolism*; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase/genetics; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase/metabolism*; Animals; Computational Biology; CpG Islands; Cytosine/analogs & derivatives*; Cytosine/metabolism; DNA Methylation; DNA/genetics; Epigenesis, Genetic; Humans; Molecular Structure; Oxidation-Reduction