1. Division of Molecular Embryology,
2. Division of Epigenetics, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
3. These authors contributed equally to this work.
4. Present address: Department of Biological Sciences and Biotechnology, Tsinghua University, 100084 Beijing, China.

Correspondence to: Christof Niehrs¹ Correspondence and requests for materials should be addressed to C.N. (Email: niehrs@dkfz.de).

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 controversial^{1, 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 growth^{3, 4}, 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 oocytes⁵, 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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