The miR-17–92a cluster, also known as ‘oncomiR-1’, is an RNA transcript that plays a pivotal regulatory role in cellular processes, including the cell cycle, proliferation and apoptosis. Its dysregulation underlies the development of several cancers. Oncomir-1 comprises six constituent miRNAs, each processed with different efficiencies as a function of both developmental time and tissue type. The structural mechanisms that regulate such differential processing are unknown, and this has impeded our understanding of the dysregulation of oncomiR-1 in pathophysiology. By probing the sensitivity of each nucleotide in oncomiR-1 to reactive small molecules, we present a secondary structural map of this RNA at single-nucleotide resolution. The secondary structure and solvent accessible regions of oncomiR-1 reveal that most of its primary microRNA domains are suboptimal substrates for Drosha-DGCR8, and therefore resistant to microprocessing. The structure indicates that the binding of trans-acting factors is required to remodel the tertiary organization and unmask cryptic primary microRNA domains to facilitate their processing into pre-microRNAs.

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单核苷酸分辨率下oncomiR-1的结构图

miR-17–92a簇，也称为“ oncomiR-1”，是一种RNA转录物，在细胞过程（包括细胞周期，增殖和凋亡）中起着关键的调节作用。其失调是几种癌症发展的基础。Oncomir-1包含六个组成的miRNA，每个miRNA的加工效率均与发育时间和组织类型有关。调节这种差异处理的结构机制尚不清楚，这妨碍了我们对oncomiR-1在病理生理学中的失调的了解。通过探测oncomiR-1中每个核苷酸对反应性小分子的敏感性，我们以单核苷酸分辨率显示了该RNA的二级结构图。oncomiR-1的二级结构和溶剂可及区域显示，其主要的一级microRNA结构域对Drosha-DGCR8而言不是最理想的底物，因此对微加工具有抗性。该结构表明反式作用因子的结合是重塑三级组织和揭露隐秘一级微RNA结构域所必需的，以促进它们加工成预微RNA。