A vitamin-C-derived DNA modification catalysed by an algal TET homologue
A vitamin-C-derived DNA modification catalysed by an algal TET homologue
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由藻类 TET 同系物催化的维生素 C 衍生 DNA 修饰
DOI：
10.1038/s41586-019-1160-0
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发表时间：
2019-05-23
期刊：
影响因子：
64.8
通讯作者：
Xu, Guo-Liang
中科院分区：
文献类型：
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作者：
Xue, Jian-Huang;Chen, Guo-Dong;Xu, Guo-Liang
胞嘧啶甲基化为5-甲基胞嘧啶（5 mC）是在许多生物体中发现的普遍的DNA修饰。10 - 11易位（泰特）双加氧酶对5 mC的连续氧化导致额外的表观遗传标记级联并促进哺乳动物中DNA的去甲基化。然而，泰特同源物在其他真核生物中的酶活性和功能在很大程度上仍未被探索。在这里，我们表明，绿色藻莱茵衣藻contains一个5 mC修饰酶（CMD 1），这是一个泰特同系物和催化的甘油基部分的共轭甲基基团的5 mC通过碳-碳键，导致两个立体异构的核碱基产品。CMD 1的催化活性需要Fe（ii）及其结合基序His-X-Asp的完整性，这在Fe依赖性双加氧酶中是保守的。然而，与先前描述的使用2-酮戊二酸作为共底物的泰特酶不同，CMD 1使用l-抗坏血酸（维生素C）作为必需的共底物。维生素C将甘油基部分提供给5 mC，同时形成乙醛酸和CO2。维生素C衍生的DNA修饰存在于野生型C的基因组中。在aCMD 1突变株中，reinhardtibut的水平显著较低。CMD 1突变细胞在强光下的适应性降低。与野生型细胞相比，在CMD 1突变细胞中，在强光条件下光氧化损伤的reinhardtii被过度甲基化和下调，导致光保护性非光化学猝灭能力降低。因此，我们的研究确定了一个真核DNA碱基修饰，催化的分歧泰特同源物和意外地来自维生素C，并描述了其作为一个潜在的表观遗传标记，可能会抵消DNA甲基化的光合作用的调节作用。
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,. However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green algaChlamydomonas reinhardtiicontains 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-X-Asp, which is conserved in Fe-dependent dioxygenases. However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate, CMD1 usesl-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-typeC. reinhardtiibut at a substantially lower level in aCMD1mutant strain. The fitness ofCMD1mutant cells during exposure to high light levels is reduced.LHCSR3, a gene that is critical for the protection ofC. reinhardtiifrom photo-oxidative damage under high light conditions, is hypermethylated and downregulated inCMD1mutant 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.