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Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex

机译：RNA聚合酶II延伸复合物识别5-羧基胞嘧啶的分子基础

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摘要

DNA methylation at selective cytosine residues (5-methylcytosine (5mC)) and their removal by TET-mediated DNA demethylation are critical for setting up pluripotent states in early embryonic development(1,2). TET enzymes successively convert 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), with 5fC and 5caC subject to removal by thymine DNA glycosylase (TDG) in conjunction with base excision repair(1-6). Early reports indicate that 5fC and 5caC could be stably detected on enhancers, promoters and gene bodies, with distinct effects on gene expression, but the mechanisms have remained elusive(7,8). Here we determined the X-ray crystal structure of yeast elongating RNA polymerase II (Pol II) in complex with a DNA template containing oxidized 5mCs, revealing specific hydrogen bonds between the 5-carboxyl group of 5caC and the conserved epi-DNA recognition loop in the polymerase. This causes a positional shift for incoming nucleoside 5'-triphosphate (NTP), thus compromising nucleotide addition. To test the implication of this structural insight in vivo, we determined the global effect of increased 5fC/5caC levels on transcription, finding that such DNA modifications indeed retarded Pol II elongation on gene bodies. These results demonstrate the functional impact of oxidized 5mCs on gene expression and suggest a novel role for Pol II as a specific and direct epigenetic sensor during transcription elongation.
机译：选择性胞嘧啶残基（5-甲基胞嘧啶（5mC））处的DNA甲基化以及通过TET介导的DNA去甲基化去除它们对于在早期胚胎发育中建立多能态至关重要（1,2）。 TET酶将5mC依次转化为5-羟甲基胞嘧啶（5hmC），5-甲酰基胞嘧啶（5fC）和5-羧基胞嘧啶（5caC），其中5fC和5caC会被胸腺嘧啶DNA糖基化酶（TDG）与碱基切除修复结合去除（1 -6）。早期报道表明，在增强子，启动子和基因体上可以稳定地检测到5fC和5caC，对基因表达有明显的影响，但其机制仍然难以捉摸（7,8）。在这里，我们确定了酵母延伸RNA聚合酶II（Pol II）与含有氧化的5mC的DNA模板的复合物的X射线晶体结构，揭示了5caC的5-羧基与保守的epi-DNA识别环之间的特定氢键。聚合酶。这导致传入核苷5'-三磷酸（NTP）的位置偏移，从而损害核苷酸添加。为了测试体内这种结构见解的含义，我们确定了5fC / 5caC水平增加对转录的总体影响，发现这种DNA修饰确实延迟了基因体上Pol II的延伸。这些结果证明了氧化的5mCs对基因表达的功能影响，并暗示了Pol II在转录延伸过程中作为特定的直接表观遗传传感器的新作用。

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  • 来源
    《Nature》 |2015年第7562期|621-625|共5页
  • 作者

    Wang Lanfeng; Zhou Yu; Xu Liang; Xiao Rui; Lu Xingyu; Chen Liang; Chong Jenny; Li Hairi; He Chuan; Fu Xiang-Dong; Wang Dong;

  • 作者单位

    Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA;

    Univ Chicago, Dept Chem, Dept Biochem & Mol Biol, Chicago, IL 60637 USA|Univ Chicago, Inst Biophys Dynam, Howard Hughes Med Inst, Chicago, IL 60637 USA;

    Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA;

    Univ Chicago, Dept Chem, Dept Biochem & Mol Biol, Chicago, IL 60637 USA|Univ Chicago, Inst Biophys Dynam, Howard Hughes Med Inst, Chicago, IL 60637 USA;

    Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA;

  • 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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