BackgroundAdenosine-to-inosine (A-to-I) RNA editing, mediated by ADAR1 and ADAR2, occurs at tens of thousands to millions of sites across mammalian transcriptomes. A-to-I editing can change the protein coding potential of a transcript and alter RNA splicing, miRNA biology, RNA secondary structure and formation of other RNA species. In vivo, the editing-dependent protein recoding of GRIA2 is the essential function of ADAR2, while ADAR1 editing prevents innate immune sensing of endogenous RNAs by MDA5 in both human and mouse. However, a significant proportion of A-to-I editing sites can be edited by both ADAR1 and ADAR2, particularly within the brain where both are highly expressed. The physiological function(s) of these shared sites, including those evolutionarily conserved, is largely unknown.ResultsTo generate completely A-to-I editing-deficient mammals, we crossed the viable rescued ADAR1-editing-deficient animals (Adar1E861A/E861AIfih1−/−) with rescued ADAR2-deficient (Adarb1−/−Gria2R/R) animals. Unexpectedly, the global absence of editing was well tolerated. Adar1E861A/E861AIfih1−/−Adarb1−/−Gria2R/R were recovered at Mendelian ratios and age normally. Detailed transcriptome analysis demonstrated that editing was absent in the brains of the compound mutants and that ADAR1 and ADAR2 have similar editing site preferences and patterns.ConclusionsWe conclude that ADAR1 and ADAR2 are non-redundant and do not compensate for each other’s essential functions in vivo. Physiologically essential A-to-I editing comprises a small subset of the editome, and the majority of editing is dispensable for mammalian homeostasis. Moreover, in vivo biologically essential protein recoding mediated by A-to-I editing is an exception in mammals.

中文翻译：

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哺乳动物体内平衡不需要大部分 A-to-I RNA 编辑

背景腺苷到肌苷 (A-to-I) RNA 编辑由 ADAR1 和 ADAR2 介导，发生在哺乳动物转录组的数万到数百万个位点。A-to-I 编辑可以改变转录本的蛋白质编码潜力，并改变 RNA 剪接、miRNA 生物学、RNA 二级结构和其他 RNA 物种的形成。在体内，GRIA2 依赖于编辑的蛋白质重新编码是 ADAR2 的基本功能，而 ADAR1 编辑阻止 MDA5 在人和小鼠中对内源性 RNA 的先天免疫感应。然而，很大一部分 A-to-I 编辑站点可以被 ADAR1 和 ADAR2 编辑，特别是在两者都高度表达的大脑中。这些共享位点的生理功能，包括进化上保守的，在很大程度上是未知的。结果为了产生完全 A-to-I 编辑缺陷的哺乳动物，我们将存活的获救的 ADAR1 编辑缺陷动物 (Adar1E861A/E861AIfih1−/−) 与拯救的 ADAR2 缺陷 (Adarb1−/−Gria2R/R) 动物杂交。出乎意料的是，全球范围内没有编辑的情况得到了很好的容忍。Adar1E861A/E861AIfih1−/−Adarb1−/−Gria2R/R 在孟德尔比率和正常年龄下恢复。详细的转录组分析表明，复合突变体的大脑中不存在编辑，并且 ADAR1 和 ADAR2 具有相似的编辑位点偏好和模式。结论我们得出结论，ADAR1 和 ADAR2 是非冗余的，在体内不能补偿彼此的基本功能。生理上必不可少的 A-to-I 编辑包括编辑组的一小部分，而大部分编辑对于哺乳动物体内平衡是可有可无的。而且，