6533b828fe1ef96bd1288601

RESEARCH PRODUCT

GADD45a physically and functionally interacts with TET1

Christof NiehrsUlrike StapfSabine KienhöferLars SchomacherMark HelmAndrea SchäferMichael U. Musheev

subject

Gadd45Cancer ResearchDNA damageCell Cycle ProteinsBiologyDNA-binding proteinArticleMixed Function OxygenaseshmCchemistry.chemical_compoundCytosineLC–MS/MSProto-Oncogene ProteinsHumansImmunoprecipitationMolecular BiologyDemethylationGadd45Nuclear ProteinsOxidative DNA demethylationCell BiologyDNA MethylationDNA-Binding Proteins5-MethylcytosineDNA demethylationHEK293 CellschemistryBiochemistryGene Knockdown TechniquesDNA methylationDNA demethylation5-MethylcytosineOxidation-ReductionTETProtein BindingDevelopmental Biology

description

AbstractDNA 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.

yearjournalcountryeditionlanguage
2015-07-01Differentiation
10.1016/j.diff.2015.10.003http://dx.doi.org/10.1016/j.diff.2015.10.003