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Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation

Nature volume 445, pages 671–675 (2007)Cite this article

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. 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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Figure 1: Gadd45a activates methylation-silenced reporter plasmids.
Figure 2: Gadd45a promotes gene-specific and global DNA demethylation.
Figure 3: Gadd45a loss of function induces DNA hypermethylation.
Figure 4: Demethylation by Gadd45a involves DNA repair.

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Acknowledgements

We thank L. Sitter for help in characterizing XPG; H. Clevers, N. Giese, H. Schöler, and J. Smith for reagents; and G. Davidson and H. Steinbeisser for helpful discussions. This work was funded by the Deutsche Forschungsgemeinschaft.

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Author notes

  1. Wei Wu

    Present address: Department of Biological Sciences and Biotechnology, Tsinghua University, 100084, Beijing, China

  2. Guillermo Barreto and Andrea Schäfer: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Embryology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Guillermo Barreto, Andrea Schäfer, Suresh K. Swaminathan, Vikas Handa, Gabi Döderlein, Nicole Maltry, Wei Wu & Christof Niehrs

  2. Division of Epigenetics, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Joachim Marhold, Dirk Stach & Frank Lyko

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Supplementary Information

This file contains Supplementary Figures S1-S8 with legends, Supplementary Methods with detailed information about the materials and methods used in this report and additional references. (PDF 655 kb)

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Barreto, G., Schäfer, A., Marhold, J. et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445, 671–675 (2007). https://doi.org/10.1038/nature05515

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