Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or “arm switching”) remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3′ strand (3p) is selected instead of the 5′ strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.

链选择是微小RNA（miRNA）生物发生中的关键步骤。尽管优势链可能会根据细胞环境而变化，但这种替代链选择（或“臂切换”）的分子机制和生理意义仍然难以捉摸。在这里，我们发现miR-324是通过臂开关而受到强烈调控的miRNA之一，并确定末端尿嘧啶转移酶TUT4和TUT7是关键的调控因子。TUT4 / 7对pre-miR-324的铀酰化使DICER在pre-miRNA上重新定位并移动了切割位点。该替代处理产生具有不同末端的双链体，从中选择3'链（3p）而不是5'链（5p）。在胶质母细胞瘤中，TUT4 / 7和3p水平上调，而5p水平降低。操纵链比足以损害胶质母细胞瘤细胞增殖。这项研究揭示了尿苷化作为替代链选择中的分子开关的作用，并暗示了其治疗潜力。