title: A TDG/CBP/RARα ternary complex mediates the retinoic acid-dependent expression of DNA methylation-sensitive genes.
abstract: The thymine DNA glycosylase (TDG) is a multifunctional enzyme, which is essential for embryonic development. It mediates the base excision repair (BER) of G:T and G:U DNA mismatches arising from the deamination of 5-methyl cytosine (5-MeC) and cytosine, respectively. Recent studies have pointed at a role of TDG during the active demethylation of 5-MeC within CpG islands. TDG interacts with the histone acetylase CREB-binding protein (CBP) to activate CBP-dependent transcription. In addition, TDG also interacts with the retinoic acid receptor α (RARα), resulting in the activation of RARα target genes. Here we provide evidence for the existence of a functional ternary complex containing TDG, CBP and activated RARα. Using global transcriptome profiling, we uncover a coupling of de novo methylation-sensitive and RA-dependent transcription, which coincides with a significant subset of CBP target genes. The introduction of a point mutation in TDG, which neither affects overall protein structure nor BER activity, leads to a significant loss in ternary complex stability, resulting in the deregulation of RA targets involved in cellular networks associated with DNA replication, recombination and repair. We thus demonstrate for the first time a direct coupling of TDG's epigenomic and transcription regulatory function through ternary complexes with CBP and RARα.
authors.affiliation: Vaccine Research Institute, INSERM U955, Institut Mondor de Recherche Biomédicale, 94011 Créteil, France; Institut des Hautes Études Scientifiques, 91440 Bures sur Yvette, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Léger
authors.affiliation: Unité de Glycobiologie Structurale et Fonctionnelle - CNRS UMR 8576, Group of NMR and Structural Biology, Université Lille 1, 59655 Villeneuve d'Ascq, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Smet-Nocca
authors.affiliation: Institut des Hautes Études Scientifiques, 91440 Bures sur Yvette, France.
authors.forename: Amel
authors.initials: A
authors.lastname: Attmane-Elakeb
authors.affiliation: Unité de Glycobiologie Structurale et Fonctionnelle - CNRS UMR 8576, Neuroplasticity Team, Université Lille 1, 59655 Villeneuve d'Ascq, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Morley-Fletcher
authors.affiliation: Institut des Hautes Études Scientifiques, 91440 Bures sur Yvette, France; CNRS UMR 7224, Université Pierre et Marie Curie, 75005 Paris, France. Electronic address: arndt.benecke@upmc.fr.
authors.forename: Arndt G
authors.initials: AG
authors.lastname: Benecke
authors.affiliation: Vaccine Research Institute, INSERM U955, Institut Mondor de Recherche Biomédicale, 94011 Créteil, France; Institut des Hautes Études Scientifiques, 91440 Bures sur Yvette, France.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eilebrecht
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D044502:Thymine DNA Glycosylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D004247:DNA; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D044502:Thymine DNA Glycosylase
keywords: CREB-binding protein; Cytosine DNA methylation; Epigenomics; Retinoic acid receptor α; Thymine DNA glycosylase; Transcription regulation