Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small-RNA-mediated immune response in plants but is absent in vertebrates. Here, we show that ectopic expression of plant RDR1 can generally inhibit cancer cell proliferation. In many human primary tumors, abnormal microRNA isoforms with 1-nt-shorter 3′ ends are widely accumulated. RDR1 with nucleotidyltransferase activity can recognize and modify the problematic AGO2-free microRNA duplexes with mononucleotides to restore their 2 nt overhang structure, which eventually rescues AGO2-loading efficiency and elevates global miRNA expression to inhibit cancer cell-cycle specifically. The broad antitumor effects of RDR1, which can be delivered by an adeno-associated virus, are visualized in multiple xenograft tumor models in vivo. Altogether, we reveal the widespread accumulation of aberrant microRNA isoforms in tumors and develop a plant RDR1-mediated antitumor stratagem by editing and repairing defective microRNAs.

癌细胞的特点是无法控制细胞周期的激活，而 microRNA 缺陷会驱动肿瘤发生。RNA 依赖性 RNA 聚合酶 (RDR) 对于植物中小 RNA 介导的免疫反应至关重要，但在脊椎动物中不存在。在这里，我们表明植物 RDR1 的异位表达通常可以抑制癌细胞增殖。在许多人类原发性肿瘤中，异常的 microRNA 同种型具有 1-nt-shorter 3' 末端广泛积累。具有核苷酸转移酶活性的 RDR1 可以用单核苷酸识别和修饰有问题的无 AGO2 的 microRNA 双链体，以恢复其 2 nt 悬垂结构，最终挽救 AGO2 加载效率并提高全局 miRNA 表达以特异性抑制癌细胞周期。RDR1 的广泛抗肿瘤作用，可由腺相关病毒传递，体内。总而言之，我们揭示了异常 microRNA 亚型在肿瘤中的广泛积累，并通过编辑和修复有缺陷的 microRNA 开发了植物 RDR1 介导的抗肿瘤策略。