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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair (NER) progeria
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Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair (NER) progeria

机译：有缺陷的转录起始导致核苷酸切除修复（NER）早衰小鼠模型中的出生后生长衰竭

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摘要

Nucleotide excision repair (NER) defects are associated with cancer, developmental disorders and neurodegeneration. However, with the exception of cancer, the links between defects in NER and developmental abnormalities are not well understood. Here, we show that the ERCC1-XPF NER endonuclease assembles on active promoters in vivo and facilitates chromatin modifications for transcription during mammalian development. We find that Ercc1~(-/-) mice demonstrate striking physiological, metabolic and gene expression parallels with Taf10~(-/-) animals carrying a liver-specific transcription factor II D (TFIID) defect in transcription initiation. Promoter occupancy studies combined with expression profiling in the liver and in vitro differentiation cell assays reveal that ERCC1-XPF interacts with TFIID and assembles with POL II and the basal transcription machinery on promoters in vivo. Whereas ERCC1-XPF is required for the initial activation of genes associated with growth, it is dispensable for ongoing transcription. Recruitment of ERCC1-XPF on promoters is accompanied by promoter-proximal DNA demethylation and histone marks associated with active hepatic transcription. Collectively, the data unveil a role of ERCC1/XPF endonuclease in transcription initiation establishing its causal contribution to NER developmental disorders.
机译：核苷酸切除修复（NER）缺陷与癌症，发育障碍和神经变性相关。但是，除癌症外，NER缺陷与发育异常之间的联系尚未得到很好的理解。在这里，我们显示ERCC1-XPF NER核酸内切酶在体内的活性启动子上组装并促进染色质修饰，从而在哺乳动物发育过程中进行转录。我们发现，Ercc1〜（-/-）小鼠表现出惊人的生理，代谢和基因表达，与Taf10〜（-/-）动物在转录起始过程中携带肝脏特异性转录因子II D（TFIID）缺陷相似。启动子占用研究与肝脏中的表达谱分析和体外分化细胞分析相结合，揭示了ERCC1-XPF与TFIID相互作用，并与POL II和基础转录机制组装在一起。 ERCC1-XPF是与生长相关的基因的初始激活所必需的，而对于正在进行的转录则是必不可少的。 ERCC1-XPF在启动子上的募集伴随着启动子近端DNA的去甲基化和与活性肝转录相关的组蛋白标记。总体而言，数据揭示了ERCC1 / XPF核酸内切酶在转录起始中的作用，确立了其对NER发育障碍的因果关系。

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    Irene Kamileri; Ismene Karakasilioti; Aria Sideri; Theodoras Kosteas; Antonis Tatarakis; lannis Talianidis; George A. Garinis;

  • 作者单位

    lnstitute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013, Heraklion, Crete, Greece,Department of Biology, University of Crete, Vassilika Vouton, GR71409, Heraklion, Crete, Greece;

    lnstitute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013, Heraklion, Crete, Greece,Department of Biology, University of Crete, Vassilika Vouton, GR71409, Heraklion, Crete, Greece;

    lnstitute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013, Heraklion, Crete, Greece;

    lnstitute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013, Heraklion, Crete, Greece;

    Biomedical Sciences Research Center Al. Fleming, 16672 Vari, Greece;

    Biomedical Sciences Research Center Al. Fleming, 16672 Vari, Greece;

    lnstitute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013, Heraklion, Crete, Greece,Department of Biology, University of Crete, Vassilika Vouton, GR71409, Heraklion, Crete, Greece;

  • 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
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  • 关键词

    DNA damage; genetics; metabolism;

    机译：DNA损伤;遗传学代谢;

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