Mechanisms that regulate the activities of TET proteins.
Mechanisms that regulate the activities of TET proteins.
复制标题
调节泰特蛋白活性的机制。
DOI：
10.1007/s00018-022-04396-x
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发表时间：
2022-06-15
影响因子：
8
通讯作者：
Zhang, Jiwang
中科院分区：
文献类型：
--
作者：
Joshi, Kanak;Liu, Shanhui;Breslin, Peter S. J.;Zhang, Jiwang
双加氧酶的10 - 11易位（泰特）家族由三个成员TET 1、TET 2和TET 3组成。所有三种泰特酶都具有Fe+2和α-酮戊二酸（α-KG）依赖性双加氧酶活性，通过将5-甲基胞嘧啶（5 mC）转化为5-羟甲基胞嘧啶（5 hmC）并进一步将5 hmC氧化为5-甲酰基胞嘧啶（5 fC）和5-羧基胞嘧啶（5caC）来催化DNA去甲基化的第一步。基因敲除研究表明，所有三种泰特蛋白都参与胚胎发育过程中胎儿器官生成和出生后正常组织生成的调节。泰特蛋白通过调节关键分化和命运决定基因的表达来发挥这种作用，所述调节通过1）靶基因的启动子和增强子的酶活性依赖性DNA甲基化;和2）组蛋白修饰的酶活性非依赖性调节。相互作用的伴侣蛋白和翻译后调节机制调节泰特蛋白的活性。泰特蛋白的突变和失调参与人类疾病，特别是癌症的发病机制。本文就泰特蛋白的相互作用伴侣及其翻译后修饰的研究进展作一综述。我们还讨论了这些伴侣蛋白和修饰调节TET功能和靶基因表达的分子机制。这些信息将有助于设计用于TET突变相关疾病的靶向治疗的药物。
The ten-eleven translocation (TET) family of dioxygenases consists of three members, TET1, TET2, and TET3. All three TET enzymes have Fe+2 and α-ketoglutarate (α-KG)-dependent dioxygenase activities, catalyzing the 1st step of DNA demethylation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and further oxidize 5hmC to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Gene knockout studies demonstrated that all three TET proteins are involved in the regulation of fetal organ generation during embryonic development and normal tissue generation postnatal. TET proteins play such roles by regulating the expression of key differentiation and fate-determine genes via 1) enzymatic activity-dependent DNA methylation of the promoters and enhancers of target genes; and 2) enzymatic activity-independent regulation of histone modification. Interacting partner proteins and posttranslational regulatory mechanisms regulate the activities of TET proteins. Mutations and dysregulation of TET proteins are involved in the pathogenesis of human diseases, specifically cancers. Here, we summarize the research on the interaction partners and posttranslational modifications of TET proteins. We also discuss the molecular mechanisms by which these partner proteins and modifications regulate TET functioning and target gene expression. Such information will help in the design of medications useful for targeted therapy of TET-mutant-related diseases.
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