RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Basic Science Program, RNA Biology Laboratory, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA.
Cell Rep. 2019 Jan 8;26(2):447-459.e4. doi: 10.1016/j.celrep.2018.12.054.
MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low-grade glioma patient samples indicate that the alternative-miR-9 has a potential role in tumor progression. Furthermore, we provide evidence that distortion of pri-miRNA stems induced by asymmetric internal loops correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.
MicroRNA (miRNA) 加工始于 Drosha 切割，其保真度对于下游加工和成熟 miRNA 靶特异性至关重要。为了了解 pri-miRNA 序列和结构如何影响 Drosha 切割，我们研究了三个 pri-miR-9 同源物的成熟过程，它们编码相同的成熟 miRNA，但周围支架不同。我们表明，由于其扭曲和灵活的茎结构，pri-miR-9-1 具有独特的 Drosha 切割谱。pri-miR-9-1 的切割，而不是 pri-miR-9-2 或 pri-miR-9-3 的切割，产生具有移位种子序列的替代 miR-9，从而扩大了其靶 RNA 的范围。对低级别神经胶质瘤患者样本的分析表明，替代 miR-9 在肿瘤进展中可能具有潜在作用。此外，我们提供的证据表明，不对称内部环引起的 pri-miRNA 茎扭曲与非规范位点的 Drosha 切割相关。我们的研究表明，通过差异 Drosha 加工，pri-miRNA 同源物可以具有不同的功能。
