Biochemical reconstitution of TET1–TDG–BER-dependent active DNA demethylation reveals a highly coordinated mechanism

Weber, Alain; Krawczyk, Claudia; Robertson, Adam B.; Kuśnierczyk, Anna; Vågbø, Cathrine Broberg; Schuermann, David; Klungland, Arne; Schär, Primo

doi:10.1038/ncomms10806

Cited by 186 publications

(172 citation statements)

References 51 publications

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“…Consistently, TET1 and TDG were found to interact physically [27,98] and to be coordinated or targeted to chromatin by accessory factors such as Gadd45a (Fig. 2) [99, 100].…”

Section: Genomic Regions Enriched For 5fc and 5cac In Tdg-deficient Ementioning

confidence: 94%

Active DNA demethylation by DNA repair: Facts and uncertainties

2016

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Pathways that control and modulate DNA methylation patterning in mammalian cells were poorly understood for a long time, although their importance in establishing and maintaining cell type-specific gene expression was well recognized. The discovery of proteins capable of converting 5-methylcytosine (5mC) to putative substrates for DNA repair introduced a novel and exciting conceptual framework for the investigation and ultimate discovery of molecular mechanisms of DNA demethylation. Against the prevailing notion that DNA methylation is a static epigenetic mark, it turned out to be dynamic and distinct mechanisms appear to have evolved to effect global and locus-specific DNA demethylation. There is compelling evidence that DNA repair, in particular base excision repair, contributes significantly to the turnover of 5mC in cells. By actively demethylating DNA, DNA repair supports the developmental establishment as well as the maintenance of DNA methylation landscapes and gene expression patterns. Yet, while the biochemical pathways are relatively well-established and reviewed, the biological context, function and regulation of DNA repair-mediated active DNA demethylation remains uncertain. In this review, we will thus summarize and critically discuss the evidence that associates active DNA demethylation by DNA repair with specific functional contexts including the DNA methylation erasure in the early embryo, the control of pluripotency and cellular differentiation, the maintenance of cell identity, and the nuclear reprogramming.

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“…Consistently, TET1 and TDG were found to interact physically [27,98] and to be coordinated or targeted to chromatin by accessory factors such as Gadd45a (Fig. 2) [99, 100].…”

Section: Genomic Regions Enriched For 5fc and 5cac In Tdg-deficient Ementioning

confidence: 94%

Active DNA demethylation by DNA repair: Facts and uncertainties

2016

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“…Alternatively, the mutagenic effect could result from the deamination of 5-mC in cooperation with its oxidation by TET2. Indeed, it has recently been shown that TET1-TDG-BER pathway could favor C > T mutagenesis when deamination of 5-mC and TET-induced oxidation of 5-mC to 5-caC occur simultaneously in the symmetrically methylated CpG [42]. This phenomenon could be enhanced in the absence of TDG.…”

Section: Impact Of Tet2-induced 5-hmc On Mutagenesismentioning

confidence: 96%

TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

Mahfoudhi¹,

Talhaoui

Cabagnols

et al. 2016

DNA Repair

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“…8,9 Results from studies such as those demonstrating in vitro recognition and excision of 5f C and 5ca C by thymine-DNA glycosidase (TDG), and increased levels of the two modifications in mouse embryonic stem cells lacking TDG, supported the notion that the oxidized species might merely be intermediates in the active reversion of the 5m C mark. [10][11][12] However, recent data revealing the association of 5hm C, 5f C, and 5ca C with regulatory elements have led to the hypothesis that they might have their own roles in gene regulation. 11,13,14 This is supported by enrichmentbased and single-base resolution sequencing studies, which show 5hm C, 5f C, and 5ca C to be enriched at various promoter, enhancer, and exon sites.…”

mentioning

confidence: 97%

Distributive Processing by the Iron(II)/α-Ketoglutarate-Dependent Catalytic Domains of the TET Enzymes Is Consistent with Epigenetic Roles for Oxidized 5-Methylcytosine Bases

et al. 2016

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The ten-eleven translocation (TET) proteins catalyze oxidation of 5-methylcytosine ((5m)C) residues in nucleic acids to 5-hydroxymethylcytosine ((5hm)C), 5-formylcytosine ((5f)C), and 5-carboxycytosine ((5ca)C). These nucleotide bases have been implicated as intermediates on the path to active demethylation, but recent reports have suggested that they might have specific regulatory roles in their own right. In this study, we present kinetic evidence showing that the catalytic domains (CDs) of TET2 and TET1 from mouse and their homologue from Naegleria gruberi, the full-length protein NgTET1, are distributive in both chemical and physical senses, as they carry out successive oxidations of a single (5m)C and multiple (5m)C residues along a polymethylated DNA substrate. We present data showing that the enzyme neither retains (5hm)C/(5f)C intermediates of preceding oxidations nor slides along a DNA substrate (without releasing it) to process an adjacent (5m)C residue. These findings contradict a recent report by Crawford et al. ( J. Am. Chem. Soc. 2016 , 138 , 730 ) claiming that oxidation of (5m)C by CD of mouse TET2 is chemically processive (iterative). We further elaborate that this distributive mechanism is maintained for TETs in two evolutionarily distant homologues and posit that this mode of function allows the introduction of (5m)C forms as epigenetic markers along the DNA.

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Biochemical reconstitution of TET1–TDG–BER-dependent active DNA demethylation reveals a highly coordinated mechanism

Cited by 186 publications

References 51 publications

Active DNA demethylation by DNA repair: Facts and uncertainties

Active DNA demethylation by DNA repair: Facts and uncertainties

TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

Distributive Processing by the Iron(II)/α-Ketoglutarate-Dependent Catalytic Domains of the TET Enzymes Is Consistent with Epigenetic Roles for Oxidized 5-Methylcytosine Bases

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