TET proteins and the control of cytosine demethylation in cancer.
TET proteins and the control of cytosine demethylation in cancer.
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DOI：
10.1186/s13073-015-0134-6
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发表时间：
2015
期刊：
影响因子：
12.3
通讯作者：
Bernard OA
中科院分区：
文献类型：
--
作者：
Scourzic L;Mouly E;Bernard OA
TEN-11易位蛋白是依赖于α的酮戊二酸双加氧酶，参与5-甲基胞嘧啶(5-MC)向5-羟甲基胞嘧啶(5-HMC)、5-甲酰胞嘧啶和5-羧基胞嘧啶的转化，揭示了胞嘧啶甲基化和去甲基化过程中的新途径。对TET2中失活突变的描述表明，细胞转化的部分原因是这种5-MC转换的放松调控。分别通过DNA甲基转移酶和异柠檬酸脱氢酶(IDH)基因突变对甲基化控制的直接和间接放松调控，以及胞嘧啶甲基化在控制正常和恶性细胞分化中的重要性，为理解癌症发展的早期步骤提供了一个概念性框架。在这里，我们综述了我们对胞嘧啶甲基化循环及其在细胞转化中的意义的最新进展，重点是Tet酶和5-HMC。正在进行的针对突变的IDH酶活性的临床试验提供了DNA甲基化是有针对性的原则证据，并将触发旨在控制癌症发展的早期和晚期的进一步治疗应用。
The discovery that ten-eleven translocation (TET) proteins are α-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine and 5-carboxycytosine has revealed new pathways in the cytosine methylation and demethylation process. The description of inactivating mutations in TET2 suggests that cellular transformation is in part caused by the deregulation of this 5-mC conversion. The direct and indirect deregulation of methylation control through mutations in DNA methyltransferase and isocitrate dehydrogenase (IDH) genes, respectively, along with the importance of cytosine methylation in the control of normal and malignant cellular differentiation have provided a conceptual framework for understanding the early steps in cancer development. Here, we review recent advances in our understanding of the cytosine methylation cycle and its implication in cellular transformation, with an emphasis on TET enzymes and 5-hmC. Ongoing clinical trials targeting the activity of mutated IDH enzymes provide a proof of principle that DNA methylation is targetable, and will trigger further therapeutic applications aimed at controlling both early and late stages of cancer development.