Department of Medical Genetics TET蛋白的组织分布 Table 1 The basic characteristics of three human TET proteins Name Other name Location Length/aa Tissue specificity Related disease TETI KIAAl676/ 10g22 2 136 Fetal heart, lung and brain, and adult Acute leukemia CXXC6/LCX skeletal muscle, thymus and ovary TET2 KIAA1546 4q24 2 002 Broadly expressed and highly expressed in Myeloproliferative diseases hematopoietic cells or neoplasms MPN) TET3 KIAA0401 2 p13. 1 1 660 colon, muscle, adrenal Gland and peripheral Not found blood lymphocytes 11
Department of Medical Genetics 11 TET蛋白的组织分布
Department of Medical Genetics TET蛋白的结构 CATALYTIC DOMAIN TET11 CXXC Cys-rich DSBH□2039 5mc oxidation TET21□ Cys-rich DSBH 191 TET3 1 CXXC Cys-rich DSBH 1803 IET家族蛋白结构 TET蛋白家族含有富含半胱氨酸区域和催化结构域两个保守区域,同时TET和TET3也含有一个CXXC型锌指结构域。 ·双核锌螯合cXXC结合域,该结构域可见于多种染色质相 互作用蛋白中。 ·TET家族蛋白是包含α-酮戊二酸的二价铁依赖性双加氧酶 12
Department of Medical Genetics TET蛋白的结构 • 双核锌螯合CXXC 结合域，该结构域可见于多种染色质相 互作用蛋白中。 • TET 家族蛋白是包含α-酮戊二酸的二价铁依赖性双加氧酶 12
Department of Medical Genetics 2.TET蛋白与DNA胞嘧啶的去甲基化 ·TET蛋白介导的DNA胞嘧啶去甲基化作用 机制 B (DNMT) (TET) (TET (TET H3 SAM NHy Pr a-KG OH NI2 O, a-KG i O. a-KG SAH CO. Succinate CO. Succinate CO. Succinate 5mc 5hmc 5fC cac The step-wise cytosine modification pathway that includes cytosine methylation by DNMTS and iterative oxidation of 5mc by TET proteins 5hmc可以被进一步氧化为5-甲酰基胞嘧啶(5 formyIcytosine,5fc及5-羧基胞 嘧啶(5- carboxylcytosine,5cac)
Department of Medical Genetics 2. TET 蛋白与DNA 胞嘧啶的去甲基化 • TET 蛋白介导的DNA 胞嘧啶去甲基化作用 机制 The step-wise cytosine modification pathway that includes cytosine methylation by DNMTs and iterative oxidation of 5mC by TET proteins. 13 5hmC 可以被进一步氧化为 5- 甲酰基胞嘧啶(5-formylcytosine,5fC)及 5- 羧基胞 嘧啶 (5-carboxylcytosine,5caC)
Department of Medical Genetics DNA脱甲基化(去甲基化)过程 PLANT 2 N(DME/ROS1) P-o O HO (BER O-P-o Base 5′ 6--o0 5mC MAMMAL O-p=0 Epo 0=P=O (TDG HO Abasic site Single- nucleotide gap o-p-0 Base 5fC cac Base excision repair of 5mc (in plants)or 5fC/5caC (in mammals)to complete DNA demethylation. Abasic site:脱碱基位点胸腺嘧啶DNA糖基化酶(TDG)识别
Department of Medical Genetics DNA 脱甲基化（去甲基化）过程 14 Base excision repair of 5mC (in plants) or 5fC/5caC (in mammals) to complete DNA demethylation. Abasic site：脱碱基位点 胸腺嘧啶DNA糖基化酶（TDG）识别
Department of Medical Genetics 主动去甲基化机制:TET蛋白对5mC 的氧化活性和碱基切除修复(BER作用 密切相关。TET蛋白能够进一步催化 氧化5hmC转化为5C和5caC,5fC和 5caC又能够在TDG的作用下被消除, 从而被C取代,完成DNA的去甲基化 15
Department of Medical Genetics • 主动去甲基化机制：TET 蛋白对 5mC 的氧化活性和碱基切除修复(BER)作用 密切相关。 TET 蛋白能够进一步催化 氧化 5 hmC 转化 为 5fC 和 5caC, 5fC 和 5caC 又能够在 TDG 的作用下被消除, 从而被 C 取代,完成 DNA 的去甲基化 15