Demystifying DNA Demethylation

DNA modifying and repair enzymes make a new connection in the mechanism of DNA demethylation. Variability and adaptability are necessary for overcoming the challenges of multicellular life. To address this need, nature has evolved a substantial enzymatic toolbox for altering cytosine within the genome. Methylation of the nucleotide cytosine (C) at the 5-position of the base has profound impacts on gene expression and cellular identity. The reverse of this process, DNA demethylation, is equally important for cleaning the genomic slate during embryogenesis or achieving rapid reactivation of previously silenced genes. Although the mechanism of DNA methylation has been rigorously established, active DNA demethylation in mammals has remained enigmatic, as disparate observations have failed to coalesce into a consistent model. Cytosine deamination, oxidation, and base excision repair enzymes have been proposed in a dizzying variety of combinations (1). Against this backdrop, two reports in this issue, by Ito et al. (2) on page 1300 and He et al. on page 1303 (3), help bring new clarity to the mechanistic model for DNA demethylation.

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[2]  Chuan He,et al.  Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine , 2011, Science.

[3]  Markus Müller,et al.  The discovery of 5-formylcytosine in embryonic stem cell DNA. , 2011, Angewandte Chemie.

[4]  A. Klein-Szanto,et al.  Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair , 2011, Cell.

[5]  G. Ming,et al.  Hydroxylation of 5-Methylcytosine by TET1 Promotes Active DNA Demethylation in the Adult Brain , 2011, Cell.

[6]  A. Bird,et al.  Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability , 2011, Nature.

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[8]  M. Biel,et al.  Tissue Distribution of 5-Hydroxymethylcytosine and Search for Active Demethylation Intermediates , 2010, PloS one.

[9]  R. Kohli.  Grand challenge commentary: The chemistry of a dynamic genome. , 2010, Nature chemical biology.

[10]  Yi Zhang,et al.  Active DNA demethylation: many roads lead to Rome , 2010, Nature Reviews Molecular Cell Biology.

[11]  Yi Zhang,et al.  Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification , 2010, Nature.

[12]  Helen M. Blau,et al.  Reprogramming towards pluripotency requires AID-dependent DNA demethylation , 2010, Nature.

[13]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1 , 2009, Science.

[14]  B. Cairns,et al.  DNA Demethylation in Zebrafish Involves the Coupling of a Deaminase, a Glycosylase, and Gadd45 , 2008, Cell.

[15]  M. Rodgers,et al.  Specificity of human thymine DNA glycosylase depends on N-glycosidic bond stability. , 2006, Journal of the American Chemical Society.