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Mammalian DNA demethylation: multiple faces and upstream regulation.
Schomacher L
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DNA cytosine methylation is a reversible epigenetic mark regulating gene expression. Aberrant methylation profiles are concomitant with developmental defects and cancer. Numerous studies in the past decade have identified enzymes and pathways responsible for active DNA demethylation both on a genome-wide as well as gene-specific scale. Recent findings have strengthened the idea that 5-methylcytosine oxidation catalyzed by members of the ten-eleven translocation (Tet1-3) oxygenases in conjunction with replication-coupled dilution of the conversion products causes the majority of genome-wide erasure of methylation marks during early development. In contrast, short and long patch DNA excision repair seems to be implicated mainly in gene-specific demethylation. Growth arrest and DNA damage-inducible protein 45 a (Gadd45a) regulates gene-specific demethylation within regulatory sequences of limited lengths raising the question of how such site specificity is achieved. A new study identified the protein inhibitor of growth 1 (Ing1) as a reader of the active chromatin mark histone H3 lysine 4 trimethylation (H3K4me3). Ing1 binds and directs Gadd45a to target sites, thus linking the histone code with DNA demethylation.
Figure 1. The multiple faces of mammalian DNA demethylation. Schematic representation of the enzymology implicated in 5-methylcytosine (5mC) demethylation. The exocyclic group at carbon 5 of each cytosine derivative is highlighted in red. C, cytosine; T, thymine; 5hmC, 5-hydroxymethylcytosine; 5fC, 5-formylcytosine; 5caC, 5-carboxylcytosine; BER: base excision repair; NER, nucleotide excision repair. Note: Direct base excision repair of 5mC and potential deamination of 5hmC to 5-hydroxymethyluracil has not been considered due to lack of experimental confirmation. For details see main text.
Figure 2. Ing1 directs Gadd45a and the demethylation machinery to H3K4me3. Proposed model for site-specific demethylation by Gadd45a. At a given gene promoter histone H3 trimethylated at lysine 4 (H3K4me3) is specifically recognized by Ing1. Gadd45a and the repair machinery are recruited through Ing1 binding. Subsequently, 5mCs are excised by DNA repair leading to DNA demethylation. Additional targeting factors may be required for the process. G45a, Gadd45a; NER, nucleotide excision repair; BER, base excision repair. Figure is from ref. 67 with permission of the authors.
Figure 2. Ing1 directs Gadd45a and the demethylation machinery to H3K4me3. Proposed model for site-specific demethylation by Gadd45a. At a given gene promoter histone H3 trimethylated at lysine 4 (H3K4me3) is specifically recognized by Ing1. Gadd45a and the repair machinery are recruited through Ing1 binding. Subsequently, 5mCs are excised by DNA repair leading to DNA demethylation. Additional targeting factors may be required for the process. G45a, Gadd45a; NER, nucleotide excision repair; BER, base excision repair. Figure is from ref. 67 with permission of the authors.
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