DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome
DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome
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DOI：
10.1038/nature21715
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发表时间：
2017-04-06
期刊：
影响因子：
64.8
通讯作者：
Akhtar, Asifa
中科院分区：
文献类型：
--
作者：
Aktas, Tugce;Ilik, Ibrahim Avsar;Akhtar, Asifa
转座元件被视为“自私的遗传元件”，但它们以不同的方式对基因调控和基因组进化做出贡献(1)。人类基因组的一半以上由转座元件组成(2)。Alu元素属于重复元素的短散布核元素(Sine)家族，超过100万个插入，它们占人类基因组的10%以上(2)。尽管Alu元素含量丰富，具有潜在的进化优势，但它们可以作为剪接受体，抑制mRNAs的翻译，并导致基因组不稳定，因此可以对宿主产生突变作用。Alu元件是RNA编辑酶ADAR(4)的主要靶点，Alu外显子的形成被核核蛋白HNRNPC5抑制，但由反向重复Alu元件形成的大量二级结构对核内RNA加工的广泛影响尚不清楚。在这里，我们展示了DHX9，一个丰富的核RNA解旋酶(7)，特异性地结合到反向重复的Alu元件上，这些元件被转录为基因的一部分。DHX9的缺失导致产生环状RNA的基因数量和环状RNA的数量增加，含有反向重复Alu元件的报告基因的翻译抑制，以及易感基因座的转录重连(在外显子之间建立几乎没有意义的新连接)。DHX9的生化纯化表明，干扰素诱导的ADAR亚型(P150)，但不是结构性表达的ADAR亚型(P110)，是RNA非依赖的相互作用伙伴。ADAR和DHX9的共同耗尽增加了双链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。我们认为它作为一种核RNA解析酶，中和了转座子插入带来的直接威胁，并允许这些元件进化为基因表达的转录后调控工具。
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.