GADD45a physically and functionally interacts with TET1

Sabine Kienhöfer, Michael U. Musheev, Ulrike Stapf, Mark Helm, Lars Schomacher, Christof Niehrs, Andrea Schäfer

Differentiation
2015 vol: 90 issue: 1-3 pp: 59-68 doi: 10.1016/j.diff.2015.10.003

Abstract
DNA demethylation plays a central role during development and in adult physiology. Different mechanisms of active DNA demethylation have been established. For example, Growth Arrest and DNA Damage 45-(GADD45) and Ten-Eleven-Translocation (TET) proteins act in active DNA demethylation but their functional relationship is unresolved. Here we show that GADD45a physically interacts–and functionally cooperates with TET1 in methylcytosine (mC) processing. In reporter demethylation GADD45a requires endogenous TET1 and conversely TET1 requires GADD45a. On GADD45a target genes TET1 hyperinduces 5-hydroxymethylcytosine (hmC) in the presence of GADD45a, while 5-formyl-(fC) and 5-carboxylcytosine (caC) are reduced. Likewise, in global analysis GADD45a positively regulates TET1 mediated mC oxidation and enhances fC/caC removal. Our data suggest a dual function of GADD45a in oxidative DNA demethylation, to promote directly or indirectly TET1 activity and to enhance subsequent fC/caC removal.

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Topics: NGadd45, TET, DNA demethylation, LC–MS/MS, hmC, Monolith – MicroScale Thermophoresis, MST, Proteins, Publications