Dnmt2的底物识别机制与生物学功能  

The substrate recognition mechanism and biological function of Dnmt2

作　　者：黄志宣 王恩多 HUANG Zhi-Xuan;WANG En-Duo(Center for Excellence in Molecular Cell Science,Chinese Academy of Science/Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,Shanghai 200031,China;University of Chinese Academy of Sciences,Beijing 100864,China;School of Life Science and Technology,Shanghai Tech University,Shanghai 201210,China)

机构地区：[1]中国科学院分子细胞科学卓越创新中心/上海生物化学与细胞生物学研究所,分子生物学国家重点实验室,上海200031 [2]中国科学院大学,北京100864 [3]上海科技大学生命科学与技术学院,上海201210

出　　处：《生命科学》2022年第4期345-356,共12页Chinese Bulletin of Life Sciences

基　　金：国家自然科学基金项目(91940302,32022040,31870811,31770842,32000919);国家重点研发计划(2017YFA0504000,2020YFA0803401)。

摘　　要：Dnmt2的同源基因首次在酵母基因组中被发现,由于其蛋白质序列与已知的DNA甲基转移酶家族成员DNMT1的序列高度同源,所以被认为是一个DNA甲基转移酶,归属于DNA甲基转.移酶家族。然而,一直没有足够的证据证明Dnmt2对DNA具有甲基转移能力。直到2006年发现Dnmt2有催化tRNA^(Asp)(GUC)甲基化修饰的能力,才确定Dnmt2的功能是一种RNA甲基转移酶,负责催化tRNA上第38位胞嘧啶的甲基化修饰,但Dnmt2识别和催化底物tRNA的分子机制仍未被全面阐明。之前研究表明,Q34可以增强Dnmt2对tRNA^(Asp)(GUC)的催化活力;王恩多课题组发现人源Dnmt2对底物tRNA的关键识别位点是G34或I34,Dnmt2识别底物依赖于底物tRNA的反密码子环、D茎和可变环的关键位点和完整的三级结构。此外,Dnmt2在细胞代谢、胚胎发育、有丝分裂、表观遗传、肿瘤与免疫等方面发挥着重要作用。该文从进化保守性、底物识别机理、蛋白质结构与功能、修饰之间的调控等方面综述了Dnmt2在RNA修饰中的最新研究进展。The homologous gene of Dnmt2 was found in the yeast genome for the first time.Due to its protein sequence being highly homologous with the amino acid sequence of the known DNA methyltransferase family member DNMT1,Dnmt2 is considered a DNA methyltransferase and belongs to DNA methyltransferase family.However,there has not been enough evidence to prove that Dnmt2 can transfer methyl groups to DNA.It was not until 2006 that Dnmt2 was discovered to catalyze tRNA^(Asp)(GUC)methylation,in which the classical biological function of Dnmt2 was determined.As an RNA methyltransferase,Dnmt2 can catalyze the methylation of cytosine at position 38 on tRNA.However,the mechanism of how Dnmt2 specifically recognizes and catalyzes the substrate tRNA remains unsolved.Previous studies have shown that Q34 can enhance the catalytic activity of Dnmt2 on tRNA^(Asp)(GUC);the key site of human Dnmt2’s recognition of substrate RNA found by our laboratory is G34 or I34 in the anticodon loop,and Dnmt2’s recognition of the substrate depends on the tertiary structure of the substrate tRNAs,as well as key sites of the D-stem and variable loop.What’s more,Dnmt2 plays important roles in cell metabolism,embryonic development,mitosis,epigenetics,tumors,and immunity.Herein,we summarize the latest research progress of Dnmt2 on RNA modification from aspects of evolutionary conservation, substrate recognitionmechanism, protein structure and function, and cross-talk between modifications.

关 键 词：甲基转移酶 TRNA Dnmt2 5-甲基胞嘧啶 分子机理 

分 类 号：Q75[生物学—分子生物学]