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Structural insight into autoinhibition and histone H3-induced activation of DNMT3A

机译：自抑制和组蛋白H3诱导的DNMT3A激活的结构见解

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摘要

DNA甲基化是在胚胎发生过程中通过重新生成的DNA甲基转移酶DNMT3A和DNMT3B确立的。在这篇论文中，Yanhui Xu及同事确定了结合到DNMT3A和组蛋白H3上的DNMT3L(DNMT3的一个没有催化活性的类似物，它刺激Dnmt3a的酶活性)的晶体结构。该结构显示了在没有组蛋白H3情况下的一个出乎意料的自抑制构形和一个由H3诱导的激活机制。%DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 A resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.
机译：DNA甲基化是在胚胎发生过程中通过重新生成的DNA甲基转移酶DNMT3A和DNMT3B确立的。在这篇论文中，Yanhui Xu及同事确定了结合到DNMT3A和组蛋白H3上的DNMT3L(DNMT3的一个没有催化活性的类似物，它刺激Dnmt3a的酶活性)的晶体结构。该结构显示了在没有组蛋白H3情况下的一个出乎意料的自抑制构形和一个由H3诱导的激活机制。%DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 A resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.

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  • 来源
    《Nature》 |2015年第7536期|640-644a3|共6页
  • 作者

    Xue Guo; Ling Wang; Jie Li; Zhanyu Ding; Jianxiong Xiao; Xiaotong Yin; Shuang He; Pan Shi; Liping Dong; Guohong Li; Changlin Tian; Jiawei Wang; Yao Cong; Yanhui Xu;

  • 作者单位

    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China,State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China;

    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China,State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China;

    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China;

    National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China;

    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China;

    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China;

    High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China,National Laboratory for Physical Science at the Microscale, University of Science and Technology of China, Hefei 230026, China,School of Life Sciences, University of Science and Technology of China, Hefei 230026, China;

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China,University of Chinese Academy of Science, Beijing 100049, China;

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China;

    High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China,National Laboratory for Physical Science at the Microscale, University of Science and Technology of China, Hefei 230026, China,School of Life Sciences, University of Science and Technology of China, Hefei 230026, China;

    State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China;

    National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

    Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China,State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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