Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome.
Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome.
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DOI：
10.1186/s13059-017-1324-x
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发表时间：
2017-10-23
期刊：
影响因子：
12.3
通讯作者：
Öhman M
中科院分区：
文献类型：
--
作者：
Daniel C;Widmark A;Rigardt D;Öhman M
腺苷到肌苷（A-to-I）RNA编辑已被证明是在哺乳动物的神经元功能以及先天免疫中起重要作用的基本事件。它需要一个大部分是双链的结构来进行催化，但对决定体内编辑效率和特异性的因素知之甚少。我们以前已经表明，一些编辑位点需要相邻的长茎环结构作为编辑诱导元件（EIE）进行有效编辑。谷氨酸受体亚基A2在几乎100%的所有转录物中在Q/R位点被编辑。我们表明，在Q/R站点的有效编辑需要在下游内含子中的EIE，由内部循环分开。此外，其他有效编辑的位点两侧都是保守的、高度结构化的EIE，我们认为这是有效编辑的一般要求，而编辑水平低的位点则缺乏EIE。这种现象不仅限于mRNA，因为非编码初级miRNA也使用EIE将阿达尔募集到特定位点。我们提出了一个模型，其中dsRNA的两个区域是有效编辑所必需的：首先，RNA茎招募阿达尔和增加酶的局部浓度，然后是一个较短，不太稳定的双链体，是有效和特异性催化的理想选择。这一发现改变了我们定义和确定A-to-I编辑底物的方式。这对于发现新的编辑位点以及解释与疾病有关的编辑改变的案例将是重要的。本文的在线版本（doi：10.1186/s13059-017-1324-x）包含补充材料，可供授权用户使用。
Adenosine to inosine (A-to-I) RNA editing has been shown to be an essential event that plays a significant role in neuronal function, as well as innate immunity, in mammals. It requires a structure that is largely double-stranded for catalysis but little is known about what determines editing efficiency and specificity in vivo. We have previously shown that some editing sites require adjacent long stem loop structures acting as editing inducer elements (EIEs) for efficient editing. The glutamate receptor subunit A2 is edited at the Q/R site in almost 100% of all transcripts. We show that efficient editing at the Q/R site requires an EIE in the downstream intron, separated by an internal loop. Also, other efficiently edited sites are flanked by conserved, highly structured EIEs and we propose that this is a general requisite for efficient editing, while sites with low levels of editing lack EIEs. This phenomenon is not limited to mRNA, as non-coding primary miRNAs also use EIEs to recruit ADAR to specific sites. We propose a model where two regions of dsRNA are required for efficient editing: first, an RNA stem that recruits ADAR and increases the local concentration of the enzyme, then a shorter, less stable duplex that is ideal for efficient and specific catalysis. This discovery changes the way we define and determine a substrate for A-to-I editing. This will be important in the discovery of novel editing sites, as well as explaining cases of altered editing in relation to disease. The online version of this article (doi:10.1186/s13059-017-1324-x) contains supplementary material, which is available to authorized users.
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