Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation.
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.
Barreto
Guillermo
G
Division of Molecular Embryology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Schäfer
Andrea
A
Marhold
Joachim
J
Stach
Dirk
D
Swaminathan
Suresh K
SK
Handa
Vikas
V
Döderlein
Gabi
G
Maltry
Nicole
N
Wu
Wei
W
Lyko
Frank
F
Niehrs
Christof
C
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
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D029867:Xenopus Proteins; C517171:Gadd45a protein, Xenopus; D000097642:GADD45 Proteins