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首页> 外文期刊>Cell cycle >Transcriptional regulation of thymine DNA glycosylase (TDG) by the tumor suppressor protein p53
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Transcriptional regulation of thymine DNA glycosylase (TDG) by the tumor suppressor protein p53

机译：肿瘤抑制蛋白p53对胸腺嘧啶DNA糖基化酶（TDG）的转录调控

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Thymine DNA glycosylase (TDG) belongs to the superfamily of uracil DNA glycosylases (UDG) and is the first enzyme in the base-excision repair pathway (BER) that removes thymine from G:T mismatches at CpG sites. This glycosylase activity has also been found to be critical for active demethylation of genes involved in embryonic development. Here we show that wild-type p53 transcriptionally regulates TDG expression. Chromatin immunoprecipitation (ChIP) and luciferase assays indicate that wild-type p53 binds to a domain of TDG promoter containing two p53 consensus response elements (p53RE) and activates its transcription. Next, we have used a panel of cell lines with different p53 status to demonstrate that TDG mRNA and protein expression levels are induced in a p53-dependent manner under different conditions. This panel includes isogenic breast and colorectal cancer cell lines with wild-type or inactive p53, esophageal squamous cell carcinoma cell lines lacking p53 or expressing a temperature-sensitive p53 mutant and normal human bronchial epithelial cells. Induction of TDG mRNA expression is accompanied by accumulation of TDG protein in both nucleus and cytoplasm, with nuclear re-localization occurring upon DNA damage in p53-competent, but not -incompetent, cells. These observations suggest a role for p53 activity in TDG nuclear translocation. Overall, our results show that TDG expression is directly regulated by p53, suggesting that loss of p53 function may affect processes mediated by TDG, thus negatively impacting on genetic and epigenetic stability.
机译：胸腺嘧啶DNA糖基化酶（TDG）属于尿嘧啶DNA糖基化酶（UDG）的超家族，是碱基切除修复途径（BER）中第一个从CpG位点的G：T错配中去除胸腺嘧啶的酶。还发现这种糖基化酶活性对于参与胚胎发育的基因的主动去甲基化至关重要。在这里，我们显示野生型p53转录调节TDG表达。染色质免疫沉淀（ChIP）和荧光素酶测定表明，野生型p53与包含两个p53共有应答元件（p53RE）的TDG启动子结构域结合并激活其转录。接下来，我们使用一组具有不同p53状态的细胞系来证明TDG mRNA和蛋白表达水平在不同条件下以p53依赖性方式被诱导。该小组包括具有野生型或无活性p53的同基因乳腺癌和结肠直肠癌细胞系，缺乏p53或表达温度敏感p53突变的食管鳞状细胞癌细胞系以及正常的人支气管上皮细胞。 TDG mRNA表达的诱导伴随着TDG蛋白在细胞核和细胞质中的积累，并且在p53感受态细胞（而非非感受态细胞）中DNA损伤后发生核重新定位。这些观察结果提示p53活性在TDG核易位中起作用。总体而言，我们的结果表明TDG的表达直接受p53调控，这表明p53功能的丧失可能影响TDG介导的过程，从而对遗传和表观遗传稳定性产生负面影响。

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