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A vitamin-C-derived DNA modification catalysed by an algal TET homologue

机译：由藻类滴管同源物催化的维生素-C衍生的DNA改性

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摘要

Methylation of cytosine to 5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. Sequential oxidation of 5mC by ten-eleven translocation (TET) dioxygenases results in a cascade of additional epigenetic marks and promotes demethylation of DNA in mammals(1,2). However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green alga Chlamydomonas reinhardtii contains a 5mC-modifying enzyme (CMD1) that is a TET homologue and catalyses the conjugation of a glyceryl moiety to the methyl group of 5mC through a carbon-carbon bond, resulting in two stereoisomeric nucleobase products. The catalytic activity of CMD1 requires Fe(ii) and the integrity of its binding motif His-XAsp, which is conserved in Fe-dependent dioxygenases(3). However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate(4), CMD1 uses l-ascorbic acid (vitamin C) as an essential co-substrate. Vitamin C donates the glyceryl moiety to 5mC with concurrent formation of glyoxylic acid and CO2. The vitamin-C-derived DNA modification is present in the genome of wild-type C. reinhardtii but at a substantially lower level in a CMD1 mutant strain. The fitness of CMD1 mutant cells during exposure to high light levels is reduced. LHCSR3, a gene that is critical for the protection of C. reinhardtii from photo-oxidative damage under high light conditions, is hypermethylated and downregulated in CMD1 mutant cells compared to wild-type cells, causing a reduced capacity for photoprotective non-photochemical quenching. Our study thus identifies a eukaryotic DNA base modification that is catalysed by a divergent TET homologue and unexpectedly derived from vitamin C, and describes its role as a potential epigenetic mark that may counteract DNA methylation in the regulation of photosynthesis.
机译：胞嘧啶的甲基化至5-甲基胞嘧啶（5MC）是许多生物体中发现的普遍存在的DNA改性。将5mc的顺序氧化在10-19℃（TET）二恶英酶导致额外的表观遗传标记，并促进DNA在哺乳动物中的去甲基化（1,2）。然而，其他真核生物中TET同源物的酶活性和功能仍然很大程度上是未开发的。在这里，我们显示绿藻衣原体Reinhardtii含有5MC改性酶（CMD1），其是TET同源物，并将甘油链部分与碳键合的甲基缀合物催化，得到两个立体异构核酸酶产物。 CMD1的催化活性需要Fe（II）和其结合基序的完整性His-XASP，其在Fe依赖性二氧化基酶（3）中保守。然而，与先前描述的TET酶不同，其使用2-氧代氟化丁烷作为共衬底（4），CMD1使用L-抗坏血酸（维生素C）作为必需的副衬底。维生素C与乙醛酸和CO 2的同时形成甘油酯部分至5MC。维生素-C衍生的DNA改性存在于野生型C. Reinhardtii的基因组中，但在CMD1突变株中的基本水平处存在于基本上。降低了CMD1突变细胞在暴露于高光水平期间的适应度。 LHCSR3，一种对高光条件下的光氧化损伤保护C. Reinhardtii至关重要的基因，与野生型电池相比，在CMD1突变细胞中进行高甲基化和下调，导致光保护非光化学淬火的能力降低。因此，我们的研究鉴定了一种真核DNA碱基改性，其被分歧的TET同源物催化，并意外地衍生自维生素C，并描述其作为潜在的表观遗传标记的作用，可以抵消光合作用调节中的DNA甲基化。

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  • 来源
    《Nature》 |2019年第7757期|581-585|共5页
  • 作者

    Xue Jian-Huang; Chen Guo-Dong; Hao Fuhua; Chen Hui; Fang Zhaoyuan; Chen Fang-Fang; Pang Bo; Yang Qing-Lin; Wei Xinben; Fan Qiang-Qiang; Xin Changpeng; Zhao Jiaohong; Deng Xuan; Wang Bang-An; Zhang Xiao-Jie; Chu Yueying; Tang Hui; Yin Huiyong; Ma Weimin; Chen Luonan; Ding Jianping; Weinhold Elmar; Kohli Rahul M.; Liu Wen; Zhu Zheng-Jiang; Huang Kaiyao; Tang Huiru; Xu Guo-Liang;

  • 作者单位

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China;

    Chinese Acad Sci Key Lab Magnet Resonance Biol Syst State Key Lab Magnet Resonance & Atom & Mol Phys Wuhan Inst Phys & Math Wuhan Hubei Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China|Univ Groningen Dept Pathol & Med Biol Univ Med Ctr Groningen Groningen Netherlands;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China;

    Chinese Acad Sci Interdisciplinary Res Ctr Biol & Chem Shanghai Inst Organ Chem Shanghai Peoples R China;

    Chinese Acad Sci State Key Lab Bioorgan & Nat Prod Chem Shanghai Inst Organ Chem Shanghai Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China;

    Chinese Acad Sci Key Lab Food Safety Res INS Shanghai Inst Biol Sci Shanghai Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China|Shanghai Tech Univ Sch Life Sci & Technol Shanghai Peoples R China;

    Chinese Acad Sci Key Lab Computat Biol Chinese Acad Sci German Max Planck Soc Partner In Shanghai Inst Biol Sci Shanghai Peoples R China;

    Shanghai Normal Univ Coll Life Sci Shanghai Peoples R China;

    Chinese Acad Sci Key Lab Algal Biol Inst Hydrobiol Wuhan Hubei Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China;

    Chinese Acad Sci Key Lab Magnet Resonance Biol Syst State Key Lab Magnet Resonance & Atom & Mol Phys Wuhan Inst Phys & Math Wuhan Hubei Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China;

    Chinese Acad Sci Key Lab Food Safety Res INS Shanghai Inst Biol Sci Shanghai Peoples R China|Shanghai Tech Univ Sch Life Sci & Technol Shanghai Peoples R China;

    Shanghai Normal Univ Coll Life Sci Shanghai Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China|Shanghai Tech Univ Sch Life Sci & Technol Shanghai Peoples R China|Chinese Acad Sci Ctr Excellence Anim Evolut & Genet Kunming Yunnan Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China|Chinese Acad Sci Natl Ctr Prot Sci Shanghai Inst Biochem & Cell Biol Shanghai Peoples R China;

    Rhein Westfal TH Aachen Inst Organ Chem Aachen Germany;

    Univ Penn Dept Med Perelman Sch Med Philadelphia PA 19104 USA|Univ Penn Dept Biochem & Biophys Perelman Sch Med Philadelphia PA 19104 USA;

    Chinese Acad Sci State Key Lab Bioorgan & Nat Prod Chem Shanghai Inst Organ Chem Shanghai Peoples R China;

    Chinese Acad Sci Interdisciplinary Res Ctr Biol & Chem Shanghai Inst Organ Chem Shanghai Peoples R China;

    Chinese Acad Sci Key Lab Algal Biol Inst Hydrobiol Wuhan Hubei Peoples R China;

    Chinese Acad Sci Key Lab Magnet Resonance Biol Syst State Key Lab Magnet Resonance & Atom & Mol Phys Wuhan Inst Phys & Math Wuhan Hubei Peoples R China|Fudan Univ State Key Lab Genet Engn Zhongshan Hosp Shanghai Peoples R China|Fudan Univ Sch Life Sci Human Phenome Inst Shanghai Int Ctr Mol Phen Collaborat Innovat Ctr Shanghai Peoples R China;

    Univ Chinese Acad Sci State Key Lab Mol Biol Ctr Excellence Mol Cell Sci Shanghai Inst Biochem & Cell Biol Chinese Acad Sc Shanghai Peoples R China|Fudan Univ Key Lab Med Epigenet & Metab Inst Biomed Sci Shanghai Med Coll Shanghai Peoples R 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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