Possible Mechanisms of Active DNA Demethylation
There are several proposed hypothetical mechanisms of active DNA demethylation: A Direct removal of 5-methylcytosine
- Direct removal of methyl group. This process has quite low thermodynamic probability.
- Removal of methylated bases (either by direct removal of methylcytosine, or through cytosine deamination followed by removal of thymine from thymine/guanosine mismatch), followed by insertion of unmethylated one using base excision repair machinery (BER).
- Removal of entire DNA patch and following filling it with new nucleotides by nucleotide excision repair (NER).
B Removal of 5-methylcytosine via further modified cytosine bases
Oxidation of the methyl group generates 5-Hydroxymethylcytosine. Several mechanisms have been proposed to mediate demethylation of 5-hydroxymethylcytosines. This base can be either deaminated by AID/Apobec enzymes to give 5-Hydroxymethyluracil. Alternatively, TET enzymes can further oxidize 5-hydroxymethylcytosine to 5-Formylcytosine and 5-Carboxylcytosine.
- Both the deamination and the oxidation products have been shown to be repaired by TDG, a glycosylase which is involved in base excision repair. A base excision mediated demethylation mechanism would yield double strand breaks if it occurs on large scale in CpG islands.
- The carboxyl and formyl groups of 5-Formylcytosine and 5-Carboxylcytosine could be enzymatically removed without excision of the base. Precedent for similar reactions is found in biosynthetic pathways.
Read more about this topic: DNA Demethylation
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