title: Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation.
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.
authors.affiliation: Division of Molecular Embryology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Barreto
authors.forename: Andrea
authors.initials: A
authors.lastname: Schäfer
authors.forename: Joachim
authors.initials: J
authors.lastname: Marhold
authors.forename: Dirk
authors.initials: D
authors.lastname: Stach
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Swaminathan
authors.forename: Vikas
authors.initials: V
authors.lastname: Handa
authors.forename: Gabi
authors.initials: G
authors.lastname: Döderlein
authors.forename: Nicole
authors.initials: N
authors.lastname: Maltry
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D019175:DNA Methylation; D004260:DNA Repair; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D013379:Substrate Specificity; D015854:Up-Regulation / Q000235:genetics*; D014981:Xenopus / Q000235:genetics* / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D029867:Xenopus Proteins; C517171:Gadd45a protein, Xenopus; D000097642:GADD45 Proteins