Recent Advances in Deciphering the Mechanisms and Biological Functions of DNA Demethylation

Comprehensive Summary 5‐Methylcytosine (5mC) is a dynamic and reversible epigenetic modification in genomic DNA of higher eukaryotes. It has been well‐established that the demethylation of 5mC occurs through the ten‐eleven translocation (TET)‐mediated oxidation of 5mC followed by thymine DNA glycosylase (TDG)‐initiated base excision repair (BER). Recent findings also have identified an alternative pathway of DNA demethylation. In this pathway, TET enzymes directly oxidize 5mC to form 5‐formylcytosine (5fC) or 5‐carboxylcytosine (5caC). These modified bases can undergo direct deformylation or decarboxylation, respectively. Additionally, DNA demethylation can also occur through the deamination of 5mC and 5hmC, resulting in the production of thymine and 5‐hydroxymethyluracil (5hmU), respectively. Various DNA demethylation pathways possess critical functional implications and roles in biological processes. This Recent Advances article will focus on the studies of mechanisms and biological functions of DNA demethylation, shedding light on the reversible nature of the epigenetic modification of 5mC.