Federal Research and Clinical Center of Physical-Chemical Medicine, 119435 Moscow, Russia.
Faculty of Biomedicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
Int J Mol Sci. 2022 May 8;23(9):5240. doi: 10.3390/ijms23095240.
Adenosine-to-inosine RNA editing is a system of post-transcriptional modification widely distributed in metazoans which is catalyzed by ADAR enzymes and occurs mostly in double-stranded RNA (dsRNA) before splicing. This type of RNA editing changes the genetic code, as inosine generally pairs with cytosine in contrast to adenosine, and this expectably modulates RNA splicing. We review the interconnections between RNA editing and splicing in the context of human cancer. The editing of transcripts may have various effects on splicing, and resultant alternatively spliced isoforms may be either tumor-suppressive or oncogenic. Dysregulated RNA splicing in cancer often causes the release of excess amounts of dsRNA into cytosol, where specific dsRNA sensors provoke antiviral-like responses, including type I interferon signaling. These responses may arrest cell division, causing apoptosis and, externally, stimulate antitumor immunity. Thus, small-molecule spliceosome inhibitors have been shown to facilitate the antiviral-like signaling and are considered to be potential cancer therapies. In turn, a cytoplasmic isoform of ADAR can deaminate dsRNA in cytosol, thereby decreasing its levels and diminishing antitumor innate immunity. We propose that complete or partial inhibition of ADAR may enhance the proapoptotic and cytotoxic effects of splicing inhibitors and that it may be considered a promising addition to cancer therapies targeting RNA splicing.
腺嘌呤到次黄嘌呤的 RNA 编辑是一种广泛存在于后生动物中的转录后修饰系统，由 ADAR 酶催化，主要发生在剪接前的双链 RNA (dsRNA) 中。这种 RNA 编辑改变了遗传密码，因为次黄嘌呤通常与胞嘧啶配对，而不是与腺嘌呤配对，这预计会调节 RNA 剪接。我们回顾了 RNA 编辑和人类癌症中剪接的相互关系。转录本的编辑可能对剪接有各种影响，并且产生的可变剪接异构体可能是抑癌的或致癌的。癌症中失调的 RNA 剪接通常会导致大量 dsRNA 释放到细胞质中，其中特定的 dsRNA 传感器引发抗病毒样反应，包括 I 型干扰素信号。这些反应可能会阻止细胞分裂，导致细胞凋亡，并在外部刺激抗肿瘤免疫。因此，已经证明小分子剪接体抑制剂可以促进抗病毒样信号，并被认为是潜在的癌症治疗方法。反过来，ADAR 的细胞质同工型可以使细胞质中的 dsRNA 脱氨，从而降低其水平并减弱抗肿瘤固有免疫。我们提出，ADAR 的完全或部分抑制可能增强剪接抑制剂的促凋亡和细胞毒性作用，并且可以被认为是针对 RNA 剪接的癌症治疗方法的有前途的补充。
