The Microprocessor complex of DROSHA and DGCR8 initiates the biosynthesis of microRNAs (miRNAs) by processing primary miRNAs (pri-miRNAs). Microprocessor can be oriented on pri-miRNAs in opposite directions to generate productive and unproductive cleavages at their basal and apical junctions, respectively. However, only the productive cleavage gives rise to miRNAs. A single nucleotide polymorphism (SNP, rs2910164) in pri-mir-146a is associated with various human diseases. Although this SNP was found to reduce the expression of miRNA, it is still not known if it affects the activity of Microprocessor directly, and how it functions. In this study, we revealed that the SNP created an unexpected mGHG motif at the apical junction of pri-mir-146a. This mGHG motif interacted with the double-stranded RNA-binding domain (dsRBD) of DROSHA, switching its orientation on pri-mir-146a from the basal to the apical junction. As a result, the SNP facilitated Microprocessor to cleave SNP-pri-mir-146a at its unproductive sites. Our findings help to elucidate the molecular mechanism that explains how the disease-associated SNP modulates the biogenesis of pri-mir-146a and thereby affects its cellular functions.

中文翻译：

---

人类疾病相关的单核苷酸多态性改变了 pri-mir-146a 上 DROSHA 的方向

DROSHA 和 DGCR8 的微处理器复合物通过处理初级 miRNA (pri-miRNA) 启动 microRNA (miRNA) 的生物合成。微处理器可以以相反的方向在 pri-miRNA 上定向，以分别在其基底和顶端连接处产生生产性和非生产性切割。然而，只有生产性切割会产生 miRNA。pri-mir-146a 中的单核苷酸多态性（SNP，rs2910164）与各种人类疾病有关。虽然发现该 SNP 会降低 miRNA 的表达，但它是否直接影响微处理器的活动以及它如何发挥作用尚不清楚。在这项研究中，我们发现 SNP 在 pri-mir-146a 的顶端连接处产生了一个意想不到的 mGHG 基序。这个 mGHG 基序与 DROSHA 的双链 RNA 结合域 (dsRBD) 相互作用，将其在 pri-mir-146a 上的方向从基底连接到顶端连接处。结果，SNP 促进微处理器在其非生产性位点切割 SNP-pri-mir-146a。我们的发现有助于阐明解释疾病相关 SNP 如何调节 pri-mir-146a 的生物发生从而影响其细胞功能的分子机制。