Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
Nat Commun. 2020 Feb 7;11(1):799. doi: 10.1038/s41467-020-14621-5.
RNA editing and splicing are the two major processes that dynamically regulate human transcriptome diversity. Despite growing evidence of crosstalk between RNA editing enzymes (mainly ADAR1) and splicing machineries, detailed mechanistic explanations and their biological importance in diseases, such as cancer are still lacking. Herein, we identify approximately a hundred high-confidence splicing events altered by ADAR1 and/or ADAR2, and ADAR1 or ADAR2 protein can regulate cassette exons in both directions. We unravel a binding tendency of ADARs to dsRNAs that involves GA-rich sequences for editing and splicing regulation. ADAR1 edits an intronic splicing silencer, leading to recruitment of SRSF7 and repression of exon inclusion. We also present a mechanism through which ADAR2 binds to dsRNA formed between GA-rich sequences and polypyrimidine (Py)-tract and precludes access of U2AF65 to 3' splice site. Furthermore, we find these ADARs-regulated splicing changes per se influence tumorigenesis, not merely byproducts of ADARs editing and binding.
RNA 编辑和剪接是动态调节人类转录组多样性的两个主要过程。尽管有越来越多的证据表明 RNA 编辑酶（主要是 ADAR1）与剪接机制之间存在串扰，但在疾病（如癌症）中，其详细的机制解释及其生物学重要性仍不清楚。在此，我们鉴定了大约 100 种由 ADAR1 和/或 ADAR2 改变的高可信度剪接事件，并且 ADAR1 或 ADAR2 蛋白可以双向调节盒式外显子。我们揭示了 ADAR 与 dsRNA 的结合倾向，涉及用于编辑和剪接调节的富含 GA 的序列。ADAR1 编辑一个内含子剪接沉默子，导致 SRSF7 的募集和外显子包含的抑制。我们还提出了一种 ADAR2 结合富含 GA 序列和嘧啶（Py）-tract 之间形成的 dsRNA 并阻止 U2AF65 接近 3' 剪接位点的机制。此外，我们发现这些 ADAR 调节的剪接变化本身会影响肿瘤发生，而不仅仅是 ADAR 编辑和结合的副产物。
