Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation

Guillermo Barreto, Andrea Schäfer, Joachim Marhold, Dirk Stach, Suresh K. Swaminathan, Vikas Handa, Gabi Döderlein, Nicole Maltry, Wei Wu, Frank Lyko, Christof Niehrs

Research output: Contribution to journalArticlepeer-review

577 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)671-675
Number of pages5
JournalNature
Volume445
Issue number7128
DOIs
StatePublished - Feb 8 2007
Externally publishedYes

Bibliographical note

Funding Information:
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.

Fingerprint

Dive into the research topics of 'Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation'. Together they form a unique fingerprint.

Cite this