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DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome

机译：DHX9抑制源自人类基因组Alu入侵的RNA加工缺陷

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摘要

Transposable elements are viewed as 'selfish genetic elements', yet they contribute to gene regulation and genome evolution in diverse ways(1). More than half of the human genome consists of transposable elements(2). Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome(2). Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability(3). Alu elements are the main targets of the RNA-editing enzyme ADAR(4) and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC5, but the broad effect of massive secondary structures formed by inverted-repeat Alu elements on RNA processing in the nucleus remains unknown. Here we show that DHX9, an abundant(6) nuclear RNA helicase(7), binds specifically to inverted-repeat Alu elements that are transcribed as parts of genes. Loss of DHX9 leads to an increase in the number of circular-RNA-producing genes and amount of circular RNAs, translational repression of reporters containing inverted-repeat Alu elements, and transcriptional rewiring (the creation of mostly nonsensical novel connections between exons) of susceptible loci. Biochemical purifications of DHX9 identify the interferon-inducible isoform of ADAR (p150), but not the constitutively expressed ADAR isoform (p110), as an RNA-independent interaction partner. Co-depletion of ADAR and DHX9 augments the double-stranded RNA accumulation defects, leading to increased circular RNA production, revealing a functional link between these two enzymes. Our work uncovers an evolutionarily conserved function of DHX9. We propose that it acts as a nuclear RNA resolvase that neutralizes the immediate threat posed by transposon insertions and allows these elements to evolve as tools for the post-transcriptional regulation of gene expression.
机译：转座因子被视为“自私的遗传元素”，但它们以多种方式促进基因调控和基因组进化（1）。人类基因组的一半以上由转座因子组成（2）。 Alu元素属于短散布的核元素（SINE）重复元素家族，插入量超过100万，占人类基因组的10％以上（2）。尽管Alu元素丰富且具有潜在的进化优势，但它们可以作为宿主诱变因子，因为它们可以充当剪接受体，抑制mRNA的翻译并引起基因组不稳定（3）。 Alu元素是RNA编辑酶ADAR（4）的主要靶标，并且Alu外显子的形成被核糖核蛋白HNRNPC5抑制，但是由反向重复Alu元素形成的大量二级结构对RNA加工的广泛影响。细胞核仍然未知。在这里，我们显示DHX9，一个丰富的（6）核RNA解旋酶（7），特异性结合转录为基因一部分的反向重复Alu元素。 DHX9的缺失会导致易感基因的环状RNA产生基因数量和环状RNA数量增加，包含反向重复Alu元件的报告基因的翻译抑制以及易感基因的转录重新接线（在外显子之间形成大多数无意义的新连接）位点。 DHX9的生化纯化可鉴定ADAR的干扰素诱导型（p150），而不是组成型表达的ADAR异构体（p110），它是RNA无关的相互作用伴侣。 ADAR和DHX9的共耗竭增加了双链RNA积累缺陷，导致环状RNA产量增加，揭示了这两种酶之间的功能联系。我们的工作揭示了DHX9在进化上的保守功能。我们建议，它作为核RNA分解酶，可中和转座子插入所造成的直接威胁，并允许这些元件演变为基因表达的转录后调控工具。

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  • 来源
    《Nature》 |2017年第7648期|115-119|共5页
  • 作者

    Aktas Tugce; Ilik Ibrahim Avsar; Maticzka Daniel; Bhardwaj Vivek; Rodrigues Cecilia Pessoa; Mittler Gerhard; Manke Thomas; Backofen Rolf; Akhtar Asifa;

  • 作者单位

    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany;

    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany;

    Albert Ludwigs Univ, Inst Informat, Freiburg, Germany;

    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany|Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany;

    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany|Univ Freiburg, Fac Biol, D-79104 Freiburg, Germany;

    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany;

    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany;

    Albert Ludwigs Univ, Inst Informat, Freiburg, Germany;

    Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany;

  • 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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