Molecular enzymology of mammalian DNA methyltransferases.
Molecular enzymology of mammalian DNA methyltransferases.
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DOI：
10.1007/3-540-31390-7_7
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发表时间：
2006
影响因子：
--
通讯作者：
A. Jeltsch
中科院分区：
文献类型：
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作者：
A. Jeltsch
DNA 甲基化是哺乳动物 DNA 的重要修饰，参与基因调控、发育、基因组防御和疾病。在哺乳动物中，已发现 3 个 DNA 甲基转移酶 (MTase) 家族，其中包括（迄今为止）4 个成员：Dnmt1、Dnmt2、Dnmt3A 和 Dnmt3B。此外，Dnmt3L 已被确定为 Dnmt3A 和 Dnmt3B 酶的刺激剂。在这篇综述中，描述了哺乳动物 DNA MTase 的酶学，首先描述了涉及共价催化和碱基翻转的催化机制。随后，讨论了哺乳动物酶的重要机制特征，包括 Dnmt1 对半甲基化靶位点的特异性、Dnmt3A、Dnmt3B 和 Dnmt2 的靶序列特异性以及 Dnmt3A 和 Dnmt3B 的侧翼序列偏好。此外，还回顾了 Dnmt1、Dnmt3A 和 Dnmt3B 甲基化反应的持续过程。最后，描述了哺乳动物 MTase 催化活性的控制，包括通过其 N 端结构域调节 Dnmt1 的活性以及 Dnmt3A 和 Dnmt3B 与 Dnmt3L 的相互作用。描述了 Dnmt1 在未修饰位点甲基化的变构激活。只要有可能，就会指出酶的生化特性与其在细胞中的生理功能之间的相关性。
DNA methylation is an essential modification of DNA in mammals that is involved in gene regulation, development, genome defence and disease. In mammals 3 families of DNA methyltransferases (MTases) comprising (so far) 4 members have been found: Dnmt1, Dnmt2, Dnmt3A and Dnmt3B. In addition, Dnmt3L has been identified as a stimulator of the Dnmt3A and Dnmt3B enzymes. In this review the enzymology of the mammalian DNA MTases is described, starting with a depiction of the catalytic mechanism that involves covalent catalysis and base flipping. Subsequently, important mechanistic features of the mammalian enzyme are discussed including the specificity of Dnmt1 for hemimethylated target sites, the target sequence specificity of Dnmt3A, Dnmt3B and Dnmt2 and the flanking sequence preferences of Dnmt3A and Dnmt3B. In addition, the processivity of the methylation reaction by Dnmt1, Dnmt3A and Dnmt3B is reviewed. Finally, the control of the catalytic activity of mammalian MTases is described that includes the regulation of the activity ofDnmt1 by its N-terminal domain and the interaction of Dnmt3A and Dnmt3B with Dnmt3L. The allosteric activation of Dnmt1 for methylation at unmodified sites is described. Wherever possible, correlations between the biochemical properties of the enzymes and their physiological functions in the cell are indicated.