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Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11112-7. Epub 2006 Jul 13.

Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks.

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Institut Jacques Monod du Centre National de la Recherche Scientifique, Universités Paris 6-7, Tour 43, 2 Place Jussieu, 75251 Paris Cedex 05, France.


Cytosine methylation at CpG dinucleotides contributes to the epigenetic maintenance of gene silencing. Dynamic reprogramming of DNA methylation patterns is believed to play a key role during development and differentiation in vertebrates. The mechanisms of DNA demethylation remain unclear and controversial. Here, we present a detailed characterization of the demethylation of an endogenous gene in cultured cells. This demethylation is triggered in a regulatory region by a transcriptional activator, the glucocorticoid receptor. We show that DNA demethylation is an active process, occurring independently of DNA replication, and in a distributive manner without concerted demethylation of cytosines on both strands. We demonstrate that the DNA backbone is cleaved 3' to the methyl cytidine during demethylation, and we suggest that a DNA repair pathway may therefore be involved in this demethylation.

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