ADARs 在癌症的环状转录组中起重要调节作用。
ADARs act as potent regulators of circular transcriptome in cancer.
机构信息
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
出版信息
Nat Commun. 2022 Mar 21;13(1):1508. doi: 10.1038/s41467-022-29138-2.
Circular RNAs (circRNAs) are produced by head-to-tail back-splicing which is mainly facilitated by base-pairing of reverse complementary matches (RCMs) in circRNA flanking introns. Adenosine deaminases acting on RNA (ADARs) are known to bind double-stranded RNAs for adenosine to inosine (A-to-I) RNA editing. Here we characterize ADARs as potent regulators of circular transcriptome by identifying over a thousand of circRNAs regulated by ADARs in a bidirectional manner through and beyond their editing function. We find that editing can stabilize or destabilize secondary structures formed between RCMs via correcting A:C mismatches to I(G)-C pairs or creating I(G).U wobble pairs, respectively. We provide experimental evidence that editing also favors the binding of RNA-binding proteins such as PTBP1 to regulate back-splicing. These ADARs-regulated circRNAs which are ubiquitously expressed in multiple types of cancers, demonstrate high functional relevance to cancer. Our findings support a hitherto unappreciated bidirectional regulation of circular transcriptome by ADARs and highlight the complexity of cross-talk in RNA processing and its contributions to tumorigenesis.
环状 RNA（circRNAs）是通过头尾反向剪接产生的，主要由环状 RNA侧翼内含子中的反向互补匹配（RCMs）碱基配对介导。已知腺苷脱氨酶作用于 RNA（ADARs）通过其编辑功能结合双链 RNA 进行腺嘌呤到肌苷（A-to-I）的 RNA 编辑。在这里，我们通过鉴定超过一千个 ADARs 双向调控的 circRNAs，将 ADARs 鉴定为环状转录组的有效调节剂，这些 circRNAs 的调控作用超越了其编辑功能。我们发现，编辑可以通过纠正 A:C 错配为 I(G)-C 对或分别创建 I(G).U 摆动对，来稳定或破坏 RCMs 之间形成的二级结构。我们提供了实验证据表明，编辑还有利于 RNA 结合蛋白（如 PTBP1）的结合，从而调节反向剪接。这些在多种类型的癌症中广泛表达的 ADARs 调控的 circRNAs，对癌症具有很高的功能相关性。我们的研究结果支持 ADARs 对环状转录组的双向调控，突显了 RNA 加工中相互作用的复杂性及其对肿瘤发生的贡献。
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