上海交通大学学报（医学版）

上海交通大学学报（医学版）

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Tet：基于DNA去甲基化的全新抗肿瘤药物靶标

龚蔚，孟周文理*，田娜，林冠乔，付天然，张良   

  1. 上海交通大学 基础医学院药理学教研室，上海 200025
  • 出版日期:2017-04-28 发布日期:2017-05-04
  • 通讯作者: 张良，电子信箱：liangzhang2014@sjtu.edu.cn。
  • 作者简介:龚蔚（1996—），女，本科生；电子信箱：gwsjtu2014@163.com。孟周文理（1995—），男，本科生；电子信箱：yzmzwl@yeah.net。*为共同第一作者。
  • 基金资助:

    国家自然科学基金（21572133）；上海交通大学医学院“大学生创新训练项目”第十期（2016008）

Tet: novel anti-tumor drug target based on DNA demethylation

GONG Wei, MENG-ZHOU Wen-li*, TIAN Na, LIN Guan-qiao, FU Tian-ran, ZHANG Liang   

  1. Department of Pharmacology, Basic Medicine Faculty of Shanghai Jiao Tong University, Shanghai 200025, China
  • Online:2017-04-28 Published:2017-05-04
  • Supported by:

    National Natural Science Foundation of China, 21572133; The 10th Undergraduate Training Programs for Innovation of Shanghai Jiao Tong University School of Medicine, 2016008

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摘要：

Tet蛋白属于α-酮戊二酸 (α-KG) 和亚铁离子 (Fe2+) 依赖的双加氧酶家族。Tet特异识别基因组DNA上5-甲基胞嘧啶 (5mC) 的甲基并进行催化氧化，是哺乳动物基因组DNA主动去甲基化途径中唯一被发现的关键因子。通过调控基因组5mC的动态平衡分布，Tet在胚胎发育早期基因调控和胚胎干细胞定向分化中至关重要，其表达和功能异常与包括骨髓增生异常综合征、慢性骨髓单核细胞性白血病和急性白血病在内的多种血液恶性肿瘤以及实体肿瘤有密切关系。因此，Tet及其介导的
DNA去甲基化是全新的抗肿瘤靶向药物靶标。对于Tet生物功能和催化机制的研究将有助于深入了解与DNA去甲基化途径相关肿瘤的发生和发展机制，同时也为
研发全新的抗肿瘤靶向药物提供参考。

关键词: DNA去甲基化, Tet蛋白, 5-羟甲基胞嘧啶, 胚胎干细胞, 抗肿瘤

Abstract:

Tet (ten-eleven translocation) proteins belong to α-ketoglutaric acid (α-KG or 2-OG) and Fe2+ dependent dioxygenases. Tets are found to be involved in the unique mammalian DNA active demethylation process by specifically oxidizing the methyl group of 5-methylcytosine (5mC) in mammalian genome, and play critical roles in gene regulation in early embryonic development and stem cell differentiation via regulating the dynamic balance distribution of 5mC. Abnormal expression and function of Tets are closely associated with various hematological malignances, including myelodysplastic syndrome, chronic myelomonocytic leukemia, and acute lymphoblastic leukemia, as well as solid tumors. Hence, Tets and Tets-mediated DNA demethylation are novel anti-tumor drug targets. Investigation of biological function and catalytic mechanism of Tets is helpful for further understanding mechanisms of tumor incidence and development relevant to DNA demethylation pathway and can provide reference for developing new anti-tumor targeted drugs.

Key words: DNA demethylation, ten eleven translocation proteins, 5-hydroxymethylcytosine, stem cells, anti-tumor