5-Methylcytosine DNA demethylation: more than losing a methyl group

Demethylation of 5-methylcytosine in DNA is integral to the maintenance of an intact epigenome. The balance between the presence or absence of 5-methylcytosine determines many physiological aspects of cell metabolism, with a turnover that can be measured in minutes to years. Biochemically, addition of the methyl group is shared among all living kingdoms and has been well characterized, whereas the removal or reversion of this mark seems diverse and much less understood. Here, we present a summary of how DNA demethylation can be initiated directly, utilizing the ten-eleven translocation (TET) family of proteins, activation-induced deaminase (AID), or other DNA modifying enzymes, or indirectly, via transcription, RNA metabolism, or DNA repair; how intermediates in those pathways are substrates of the DNA repair machinery; and how demethylation pathways are linked and possibly balanced, avoiding mutations.