MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression and their dysfunction is often associated with cancer. Alongside the canonical miRNA biogenesis pathway involving stepwise processing and export of pri- and pre-miRNA transcripts by the microprocessor complex, Exportin 5 and Dicer, several alternative mechanisms of miRNA production have been described. Here, we reveal that the atypical box C/D snoRNA U3, which functions as a scaffold during early ribosome assembly, is a miRNA source. We show that a unique stem–loop structure in the 5′ domain of U3 is processed to form short RNA fragments that associate with Argonaute. miR-U3 production is independent of Drosha, and an increased amount of U3 in the cytoplasm in the absence of Dicer suggests that a portion of the full length snoRNA is exported to the cytoplasm where it is efficiently processed into miRNAs. Using reporter assays, we demonstrate that miR-U3 can act as a low proficiency miRNA in vivo and our data support the 3′ UTR of the sortin nexin SNX27 mRNA as an endogenous U3-derived miRNA target. We further reveal that perturbation of U3 snoRNP assembly induces miR-U3 production, highlighting potential cross-regulation of target mRNA expression and ribosome production.

中文翻译：

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人框C / D snoRNA U3是miRNA来源，而miR-U3调节sortin nexin 27的表达。

微小RNA（miRNA）是真核基因表达的重要调节剂，其功能障碍通常与癌症有关。除了经典的miRNA生物发生途径外，还涉及微处理器复合物Exportin 5和Dicer逐步处理和输出pri-和pre-miRNA转录本，还描述了产生miRNA的几种替代机制。在这里，我们发现非典型框C / D snoRNA U3是miRNA来源，在早期核糖体组装过程中起支架作用。我们显示，U3的5'域中的独特茎-环结构经过加工形成了与Argonaute相关的短RNA片段。miR-U3的生产独立于Drosha，在没有Dicer的情况下，细胞质中U3含量的增加表明全长snoRNA的一部分输出到细胞质中，在那里它被有效地加工成miRNA。使用报告基因检测，我们证明了miR-U3可以作为低水平的miRNA在体内，我们的数据支持sortin nexin SNX27 mRNA作为内源性U3衍生的miRNA靶标的3'UTR。我们进一步揭示，U3 snoRNP程序集的扰动诱导miR-U3的产生，突出了潜在的靶mRNA表达和核糖体产生的交叉调节。