Epigenetic modifications in DNA could mimic oxidative DNA damage: A double-edged sword.

Methylation of cytosine at the C5 position (5mC) represents an epigenetic modification that plays a fundamental role in embryonic development, transcriptional regulation, and other processes. It can also be a mutational hotspot at CpG dinucleotides as a result of spontaneous hydrolytic deamination of 5mC to thymine. The resulting G · T mismatch pair is recognized by thymine DNA glycosylase (TDG) and revereted to a G · C pair. Recent studies have shown that 5mC is consecutively catalyzed into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) by a DNA dioxygenase from the ten-eleven translocation (TET) family. Two oxidative cytosine derivatives, 5fC and 5caC, are eliminated by TDG during active DNA demethylation. Therefore, TDG has versatile roles in epigenetic regulation to control the gene expression as well as the DNA repair pathway to prevent mutagenesis. 5fC and 5caC serve as intermediate products of active DNA demethylation and also behave as DNA damages that threaten genomic integrity. Here, we discuss the potential functions of 5mC oxidative derivatives in epigenetic modification and DNA damage.