A TDG/CBP/RAR伪 Ternary Complex Mediates the Retinoic Acid-dependent Expression of DNA Methylation-sensitive Genes

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• 作者：Hé ; lè ; ne Lé ; ger¹ ; ² ; Caroline Smet-Nocca³ ; Amel Attmane-Elakeb² ; Sara Morley-Fletcher⁴ ; Arndt G. Benecke² ; ⁵ ; ^{arndt.benecke@upmc.fr" class="auth_mail} ; Sebastian Eilebrecht¹ ; ²
• 关键词：CREB-binding protein ; Thymine DNA glycosylase ; Retinoic acid receptor 伪 ; Transcription regulation ; Cytosine DNA methylation ; Epigenomics
• 刊名：Genomics, Proteomics Bioinformatics
• 出版年：February, 2014
• 年：2014
• 卷：12
• 期：1
• 页码：8-18
• 全文大小：2281 K

文摘

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 伪 (RAR伪), resulting in the activation of RAR伪 target genes. Here we provide evidence for the existence of a functional ternary complex containing TDG, CBP and activated RAR伪. 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鈥檚 epigenomic and transcription regulatory function through ternary complexes with CBP and RAR伪.