Gadd45a promtoes epigenetic gene activation by repair-mediated DNA demethylation

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Abstract

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 controversial1,2. 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 growth3,4, has a key role in active DNA demethylation.Gadd45aoverexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation.Gadd45aknockdown silences gene expression and leads to DNA hypermethylation. During active demethylation ofoct4inXenopus laevisoocytes5, 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.

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