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Gadd45a Promotes Epigenetic Gene Activation by Repair-Mediated DNA Demethylation
By Trevor | March 5, 2007
Nature has published a letter from researchers at the German Cancer Research Center involving their implication of the gene Gadd45a in one of the black boxes of epigenetic mechanisms: demethylation.
DNA methylation is an epigenetic modification that is essential for gene silencing and genome stability in many organisms. Although methyltransferases that promote DNA methylation are well characterized, the molecular mechanism underlying active DNA demethylation is poorly understood and controversial. Here we show that Gadd45a (growth arrest and DNA-damage-inducible protein 45 alpha), a nuclear protein involved in maintenance of genomic stability, DNA repair and suppression of cell growth, has a key role in active DNA demethylation. Gadd45a overexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation. Gadd45a knockdown silences gene expression and leads to DNA hypermethylation. During active demethylation of oct4 in Xenopus laevis oocytes, Gadd45a is specifically recruited to the site of demethylation. Active demethylation occurs by DNA repair and Gadd45a interacts with and requires the DNA repair endonuclease XPG. We conclude that Gadd45a relieves epigenetic gene silencing by promoting DNA repair, which erases methylation marks.
One of the experiments from this paper seem to support the recent finding that demethylation of the proximal-promoter region is required for active transcription.
ScienceDaily offers a summary of this research adapted from a press release from the German Cancer Research Center. Link
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Topics: chromatin, commentary, methylation, news links, research articles |
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