DNA demethylation pathways: Additional players and regulators

Abstract

DNA demethylation can occur passively by "dilution" of methylation marks by DNA replication, or actively and independently of DNA replication. Direct conversion of 5-methylcytosine (5mC) to cytosine (C), as originally proposed, does not occur. Instead, active DNA methylation involves oxidation of the methylated base by ten-eleven translocations (TETs), or deamination of the methylated or a nearby base by activation induced deaminase (AID). The modified nucleotide, possibly together with surrounding nucleotides, is then replaced by the BER pathway. Recent data clarify the roles and the regulation of well-known enzymes in this process. They identify base excision repair (BER) glycosylases that may cooperate with or replace thymine DNA glycosylase (TDG) in the base excision step, and suggest possible involvement of DNA damage repair pathways other than BER in active DNA demethylation. Here, we review these new developments.

Targeting the epigenome in malignant pleural mesothelioma

“…DNA demethylation occurs passively during DNA replication (16). Furthermore, DNA is actively demethylated by ten-eleven translocations (TET) enzymes which catalyze oxidation of 5-MC to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine (17).…”

“…During malignant transformation, the total amount of methylated CpGs except for those in promoter CpG islands becomes markedly reduced (up to 50%) (9). Whereas genome wide DNA demethylation may be attributable to deficient DNA repair (18,19), decreased DNA methyltransferase 1 expression (20,21), glycosylase-mediated excision of 5-MC (16), and aberrant expression/targeting of TET proteins (22), the mechanisms mediating this phenomenon have not been fully elucidated. Genome-wide DNA demethylation facilitates de-repression of imprinted alleles, endogenous retroviruses, and transposable elements, thereby inducing genomic instability (11,23).…”

Targeted DNA demethylation in human cells by fusion of a plant 5-methylcytosine DNA glycosylase to a sequence-specific DNA binding domain

“…2 Demethylation involves either dilution of 5mC by DNA replication in the absence of methylation, designated passive DNA demethylation, or enzymatic processes for replication-independent removal of 5mC, termed active DNA demethylation. 3 Accumulating evidence suggests that DNA demethylation in mammalian cells involves iterative oxidation of 5mC by TET dioxygenases, followed by either passive replication-dependent dilution or active removal of oxidized 5mC derivatives through DNA repair (reviewed in 4,5 ). However, the emerging picture is still unclear because the magnitude of passive dilution compared to active DNA repair is unknown 2 and, moreover, oxidized forms of 5mC may behave as independent epigenetic marks on their own.…”

DNA damage and base excision repair : an important role during zebrafish embryogenesis

“…This produces a G/T mismatch which activates BER via TDG, resulting in replacement of T with unmodified cytosine (Bochtler, Kolano, and Xu 2017;Niehrs 2009). …”

“…Active DNA demethylation is an iterative process requiring the coordination of a number of enzymes, though the actual pathway is controversial. Three different pathways have been proposed in the past, though one, straight substitution of the methyl group with hydrogen, is inconsistent with chemical reaction theory (Bochtler et al 2017;Smith 2000). The other pathways all result in the generation of DNA damage requiring BER to resolve (Bochtler et al 2017).…”