Adenosine Deaminases that Act on RNA (ADARs) are a group of enzymes that catalyze the conversion of adenosines (A's) to inosines (I's) in a process known as RNA editing. Though ADARs can act on different types of RNA, editing events in coding regions of mRNA are of particular interest as I's base pair like guanosines (G's). Thus, every A-to-I change catalyzed by ADAR is read as an A-to-G change during translation, potentially altering protein sequence and function. This ability to re-code makes ADAR an attractive therapeutic tool to correct genetic mutations within mRNA. The main challenge in doing so is to re-direct ADAR's catalytic activity towards A's that are not naturally edited, a process termed Site-Directed RNA Editing (SDRE). Recently, a handful of labs have taken up this challenge and two basic strategies have emerged. The first involves redirecting endogenous ADAR to new sites by making editable structures using antisense RNA oligonucleotides. The second also utilizes antisense RNA oligonucleotides, but it uses them as guides to deliver the catalytic domain of engineered ADARs to new sites, much as CRISPR guides deliver Cas nucleases. In fact, despite the intense current focus on CRISPR-Cas9 genome editing, SDRE offers a number of distinct advantages. In the present review we will discuss these strategies in greater detail, focusing on the concepts on which they are based, how they were developed and tested, and their respective advantages and disadvantages. Though the precise and efficient re-direction of ADAR activity still remains a challenge, the systems that are being developed lay the foundation for SDRE as a powerful tool for transient genome editing.

中文翻译：

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当前使用 ADAR 进行定点 RNA 编辑的策略


作用于 RNA 的腺苷脱氨酶 (ADAR) 是一组在称为 RNA 编辑的过程中催化腺苷 (A's) 转化为肌苷 (I's) 的酶。尽管 ADAR 可以作用于不同类型的 RNA，但 mRNA 编码区的编辑事件尤其令人感兴趣，因为 I 的碱基对如鸟苷 (G)。因此，ADAR 催化的每个 A 到 I 的变化都被解读为翻译过程中的 A 到 G 的变化，可能会改变蛋白质序列和功能。这种重新编码的能力使 ADAR 成为纠正 mRNA 内基因突变的有吸引力的治疗工具。这样做的主要挑战是将 ADAR 的催化活性重新定向到未自然编辑的 A，这一过程称为定点 RNA 编辑 (SDRE)。最近，一些实验室已经接受了这一挑战，并出现了两种基本策略。第一个涉及通过使用反义 RNA 寡核苷酸构建可编辑结构，将内源 ADAR 重定向到新位点。第二种也利用反义 RNA 寡核苷酸，但它使用它们作为引导，将工程 ADAR 的催化结构域传递到新位点，就像 CRISPR 引导传递 Cas 核酸酶一样。事实上，尽管目前 CRISPR-Cas9 基因组编辑受到广泛关注，但 SDRE 仍具有许多独特的优势。在本次综述中，我们将更详细地讨论这些策略，重点关注它们所基于的概念、它们是如何开发和测试的，以及它们各自的优点和缺点。尽管 ADAR 活动的精确有效重定向仍然是一个挑战，但正在开发的系统为 SDRE 作为瞬时基因组编辑的强大工具奠定了基础。