...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation
【24h】

Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation

机译：拓扑异构酶I的减少与激活诱导的胞苷脱氨酶（AID）依赖的体细胞超突变有关

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Somatic hypermutation (SHM) and class-switch recombination (CSR) of the Ig gene require both the transcription of the locus and the expression of activation-induced cytidine deaminase (AID). During CSR, AID decreases the amount of topoisomerase I (Topi); this decrease alters the DNA structure and induces cleavage in the S region. Similarly, Top1 is involved in transcription-associated mutation at dinucleotide repeats in yeast and in triplet-repeat contraction in mammals. Here, we report that the AID-induced decrease in Topi is critical for SHM. Top1 knockdown or haploinsufficiency enhanced SHM, whereas Top1 overexpression down-regulated it. A specific Top1 inhibitor, camptothecin, suppressed SHM, indicating that Top1's activity is required for DNA cleavage. Nonetheless, suppression of transcription abolished SHM, even in cells with Top1 knockdown, suggesting that transcription is critical. These results are consistent with a model proposed for CSR and triplet instability, in which transcription-induced non-B structure formation is enhanced by Top1 reduction and provides the target for irreversible cleavage by Top1. We speculate that the mechanism for transcription-coupled genome instability was adopted to generate immune diversity when AID evolved.
机译：Ig基因的体细胞超突变（SHM）和类开关重组（CSR）需要基因座的转录和激活诱导的胞苷脱氨酶（AID）的表达。在CSR期间，AID会降低拓扑异构酶I（Topi）的量；这种减少改变了DNA结构并诱导了S区的切割。同样，Top1在酵母中与二核苷酸重复处的转录相关突变有关，在哺乳动物中与三联体重复收缩有关。在这里，我们报告说AID诱导的Topi下降对于SHM至关重要。 Top1敲低或单倍剂量不足增强了SHM，而Top1过表达下调了它。特定的Top1抑制剂喜树碱可抑制SHM，这表明DNA切割需要Top1的活性。尽管如此，即使在具有Top1敲低的细胞中，转录抑制也消除了SHM，这表明转录是至关重要的。这些结果与针对CSR和三联体不稳定性提出的模型相一致，在该模型中，转录诱导的非B结构的形成通过Top1的还原得到增强，并为Top1的不可逆切割提供了目标。我们推测，当AID进化时，采用转录偶联基因组不稳定性的机制来产生免疫多样性。

著录项

  • 来源
  • 作者

    Maki Kobayashi; Zahra Sabouri; Somayeh Sabouri; Yoko Kitawaki; Yves Pommier; Takaya Abe; Hiroshi Kiyonari; Tasuku Honjo;

  • 作者单位

    Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;

    Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;

    Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;

    Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;

    Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255;

    Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;

    Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;

    Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    DNA cleavage; non-B DNA structure;

    机译：DNA切割;非B DNA结构;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号