Jia Yingying, Nie Fen, Du Aiying, Chen Zhangcheng, Qin Yuanbo, Huang Tao, Song Xiaomin, Li Lin
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
J Mol Cell Biol. 2014 Jun;6(3):231-9. doi: 10.1093/jmcb/mju014. Epub 2014 Apr 18.
Thymine DNA glycosylase (TDG), an enzyme that initiates the repair of G/T and G/U mismatches, has been lately found crucial in embryonic development to maintain epigenetic stability and facilitate the active DNA demethylation. Here we report a novel role of TDG in Wnt signaling as a transcriptional coactivator of β-catenin/TCFs complex. Our data show that TDG binds to the transcriptional factor family LEF1/TCFs and potentiates β-catenin/TCFs transactivation, while TDG depletion suppresses Wnt3a-stimulated reporter activity or target gene transcription. Next, we show that CBP, a known coactivator, is also required for TDG function through forming a cooperative complex on target promoters. Moreover, there is an elevation of TDG levels in human colon cancer tissue, and knockdown of TDG inhibits proliferation of the colon cells. Overall, our results reveal that TDG, as a new coactivator, promotes β-catenin/TCFs transactivation and functionally cooperates with CBP in canonical Wnt signaling.
胸腺嘧啶DNA糖基化酶（TDG）是一种启动G/T和G/U错配修复的酶，最近发现它在胚胎发育中对于维持表观遗传稳定性和促进DNA主动去甲基化至关重要。在此，我们报告TDG在Wnt信号通路中的一个新作用，即作为β-连环蛋白/TCFs复合物的转录共激活因子。我们的数据表明，TDG与转录因子家族LEF1/TCFs结合并增强β-连环蛋白/TCFs的反式激活作用，而TDG缺失则抑制Wnt3a刺激的报告基因活性或靶基因转录。接下来，我们表明已知的共激活因子CBP也是TDG功能所必需的，它通过在靶启动子上形成协同复合物发挥作用。此外，人类结肠癌组织中TDG水平升高，敲低TDG可抑制结肠细胞增殖。总体而言，我们的结果表明，TDG作为一种新的共激活因子，促进β-连环蛋白/TCFs的反式激活，并在经典Wnt信号通路中与CBP在功能上协同作用。
