TAF12 recruits Gadd45a and the nucleotide excision repair complex to the promoter of rRNA genes leading to active DNA demethylation.
Many studies have detailed the repressive effects of DNA methylation on gene expression. However, the mechanisms that promote active demethylation are just beginning to emerge. Here, we show that methylation of the rDNA promoter is a dynamic and reversible process. Demethylation of rDNA is initiated by recruitment of Gadd45a (growth arrest and DNA damage inducible protein 45 alpha) to the rDNA promoter by TAF12, a TBP-associated factor that is contained in Pol I- and Pol II-specific TBP-TAF complexes. Once targeted to rDNA, Gadd45a triggers demethylation of promoter-proximal DNA by recruiting the nucleotide excision repair (NER) machinery to remove methylated cytosines. Knockdown of Gadd45a, XPA, XPG, XPF, or TAF12 or treatment with drugs that inhibit NER causes hypermethylation of rDNA, establishes heterochromatic histone marks, and impairs transcription. The results reveal a mechanism that recruits the DNA repair machinery to the promoter of active genes, keeping them in a hypomethylated state.
Schmitz
Kerstin-Maike
KM
Division of Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, INF 581, D-69120 Heidelberg, Germany.
Schmitt
Nina
N
Hoffmann-Rohrer
Urs
U
Schäfer
Andrea
A
Grummt
Ingrid
I
Mayer
Christine
C
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage; D019175:DNA Methylation / Q000235:genetics*; D004260:DNA Repair; D020459:Genes, rRNA / Q000235:genetics*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D035381:TATA-Binding Protein Associated Factors; C439070:GADD45A protein, human; D000097642:GADD45 Proteins