TET1,2,3 和 TDG 去甲基化 DNA
中文名称
通路描述
在哺乳动物细胞中，约 2-6% 的所有胞嘧啶残基和 CG 二核苷酸中的 70-80% 胞嘧啶残基在嘧啶环的 5 位点甲基化。胞嘧啶残基在 DNA 复制后由 DNA 甲基转移酶甲基化，可以通过随后的复制过程中的被动稀释进行去甲基化，也可以通过 5-甲基胞嘧啶碱基的主动修饰进行去甲基化。胞嘧啶去甲基化是发育调控的：一次去甲基化波发生在原始生殖细胞中，另一次去甲基化波发生在受精后雄性原核中通过主动去甲基化发生。
虽然一些主动去甲基化的机制仍有争议，但已在体内反复证明，5-甲基胞嘧啶的氧化后由胸腺嘧啶 DNA 糖基化酶（TDG）进行碱基切除（综述在 Wu and Zhang 2011, Franchini 等。2012, Cadet 和 Wagner 2013, Kohli 和 Zhang 2013, Ponnaluri 等。2013, Rasmussen 和 Helin 2016）。十核苷酸转位蛋白 TET1, TET2 和 TET3 是二氧合酶，首先氧化 5-甲基胞嘧啶为 5-羟甲基胞嘧啶（5-hmC）（Tahiliani 等。2009, Ito 等。2010），该物质在干细胞和神经元中含量丰富且位于特定基因组位置（Kinney 和 Pradhan 2013）。TET 蛋白可以进一步氧化 5-hmC 为 5-羰基胞嘧啶（5-fC）和 5-羧基胞嘧啶（5-caC）（He 等。2011, Ito 等。2011）。G:5-fC 和 G:5-caC 碱基对被 TDG 识别，切除 5-fC 或 5-caC 并留下无碱基位点。
TET1 在小鼠中表达于神经元，其表达依赖于神经元活动（Guo 等。2011, Kaas 等。2013, Zhang 等。2013）。TET1 也在胚胎干细胞（Ficz 等。2011, Koh 等。2011, Wu 等。2011）和小鼠原始生殖细胞中检测到，在那里它在擦除印记中发挥作用（Yamaguchi 等。2013）。TET3 在小鼠卵子和受精卵中表达，并在雄性原核中去甲基化中起必需作用（Gu 等。2011, Iqbal 等。2011）。TET2 是造血干细胞中表达最高的 TET 家族蛋白，似乎作为肿瘤抑制因子起作用。TET2 也在胚胎干细胞中表达（Koh 等。2011）。
虽然一些主动去甲基化的机制仍有争议，但已在体内反复证明，5-甲基胞嘧啶的氧化后由胸腺嘧啶 DNA 糖基化酶（TDG）进行碱基切除（综述在 Wu and Zhang 2011, Franchini 等。2012, Cadet 和 Wagner 2013, Kohli 和 Zhang 2013, Ponnaluri 等。2013, Rasmussen 和 Helin 2016）。十核苷酸转位蛋白 TET1, TET2 和 TET3 是二氧合酶，首先氧化 5-甲基胞嘧啶为 5-羟甲基胞嘧啶（5-hmC）（Tahiliani 等。2009, Ito 等。2010），该物质在干细胞和神经元中含量丰富且位于特定基因组位置（Kinney 和 Pradhan 2013）。TET 蛋白可以进一步氧化 5-hmC 为 5-羰基胞嘧啶（5-fC）和 5-羧基胞嘧啶（5-caC）（He 等。2011, Ito 等。2011）。G:5-fC 和 G:5-caC 碱基对被 TDG 识别，切除 5-fC 或 5-caC 并留下无碱基位点。
TET1 在小鼠中表达于神经元，其表达依赖于神经元活动（Guo 等。2011, Kaas 等。2013, Zhang 等。2013）。TET1 也在胚胎干细胞（Ficz 等。2011, Koh 等。2011, Wu 等。2011）和小鼠原始生殖细胞中检测到，在那里它在擦除印记中发挥作用（Yamaguchi 等。2013）。TET3 在小鼠卵子和受精卵中表达，并在雄性原核中去甲基化中起必需作用（Gu 等。2011, Iqbal 等。2011）。TET2 是造血干细胞中表达最高的 TET 家族蛋白，似乎作为肿瘤抑制因子起作用。TET2 也在胚胎干细胞中表达（Koh 等。2011）。
英文描述
TET1,2,3 and TDG demethylate DNA About 2-6% of all cytosine residues and 70-80% of cytosine residues in CG dinucleotides in mammalian cells are methylated at the 5 position of the pyrimidine ring. The cytosine residues are methylated by DNA methyltransferases after DNA replication and can be demethylated by passive dilution during subsequent replication or by active modification of the 5-methylcytosine base. Cytosine demethylation is developmentally regulated: one wave of demethylation occurs in primordial germ cells and one wave occurs by active demethylation in the male pronucleus after fertilization.
Some mechanisms of active demethylation remain controversial, however progressive oxidation of the methyl group of 5-methylcytosine followed by base excision by thymine DNA glycosylase (TDG) has been reproducibly demonstrated in vivo (reviewed in Wu and Zhang 2011, Franchini et al 2012, Cadet and Wagner 2013, Kohli and Zhang 2013, Ponnaluri et al. 2013, Rasmussen and Helin 2016). Ten-eleven translocation proteins TET1, TET2, and TET3 are dioxygenases that first oxidize 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) (Tahiliani et al. 2009, Ito et al. 2010), which is found in significant quantities and specific genomic locations in stem cells and neurons (Kinney and Pradhan 2013). TET proteins can further oxidize 5-hmC to 5-formylcytosine (5-fC) and then 5-carboxylcytosine (5-caC) (He et al. 2011, Ito et al. 2011). G:5-fC and G:5-caC base pairs are recognized by TDG, which excises the 5-fC or 5-caC and leaves an abasic site.
TET1 in mouse is expressed in neurons and its expression depends on neuronal activity (Guo et al. 2011, Kaas et al. 2013, Zhang et al. 2013). TET1 is also found in embryonic stem cells (Ficz et al. 2011, Koh et al. 2011, Wu et al. 2011) and in primordial germ cells of mice, where it plays a role in erasure of imprinting (Yamaguchi et al. 2013). TET3 is expressed in oocytes and zygotes of mice and is required for demethylation in the male pronucleus (Gu et al. 2011, Iqbal et al. 2011). TET2 is the most highly expressed TET family protein in hemopoietic stem cells and appears to act as a tumor suppressor. TET2 is also expressed in embryonic stem cells (Koh et al. 2011).
Some mechanisms of active demethylation remain controversial, however progressive oxidation of the methyl group of 5-methylcytosine followed by base excision by thymine DNA glycosylase (TDG) has been reproducibly demonstrated in vivo (reviewed in Wu and Zhang 2011, Franchini et al 2012, Cadet and Wagner 2013, Kohli and Zhang 2013, Ponnaluri et al. 2013, Rasmussen and Helin 2016). Ten-eleven translocation proteins TET1, TET2, and TET3 are dioxygenases that first oxidize 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) (Tahiliani et al. 2009, Ito et al. 2010), which is found in significant quantities and specific genomic locations in stem cells and neurons (Kinney and Pradhan 2013). TET proteins can further oxidize 5-hmC to 5-formylcytosine (5-fC) and then 5-carboxylcytosine (5-caC) (He et al. 2011, Ito et al. 2011). G:5-fC and G:5-caC base pairs are recognized by TDG, which excises the 5-fC or 5-caC and leaves an abasic site.
TET1 in mouse is expressed in neurons and its expression depends on neuronal activity (Guo et al. 2011, Kaas et al. 2013, Zhang et al. 2013). TET1 is also found in embryonic stem cells (Ficz et al. 2011, Koh et al. 2011, Wu et al. 2011) and in primordial germ cells of mice, where it plays a role in erasure of imprinting (Yamaguchi et al. 2013). TET3 is expressed in oocytes and zygotes of mice and is required for demethylation in the male pronucleus (Gu et al. 2011, Iqbal et al. 2011). TET2 is the most highly expressed TET family protein in hemopoietic stem cells and appears to act as a tumor suppressor. TET2 is also expressed in embryonic stem cells (Koh et al. 2011).
所含基因
4 个基因