A Mechanism for microRNA Arm Switching Regulated by Uridylation
A Mechanism for microRNA Arm Switching Regulated by Uridylation
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DOI：
10.1016/j.molcel.2020.04.030
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发表时间：
2020-06-18
期刊：
影响因子：
16
通讯作者：
Kim, V. Narry
中科院分区：
文献类型：
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作者：
Kim, Haedong;Kim, Jimi;Kim, V. Narry
链选择是microRNA（miRNA）生物合成的关键步骤。虽然主导链可能会根据细胞环境而改变，但这种替代链选择（或“臂转换”）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是通过臂转换强烈调节的miRNA之一，并确定末端尿苷酰转移酶TUT 4和TUT 7是关键调节剂。TUT 4/7对pre-miR-324的尿苷酸化使DICER重新定位在pre-miRNA上并移动切割位点。这种替代加工产生具有不同末端的双链体，从该末端选择3'链（3 p）而不是5'链（5 p）。在胶质母细胞瘤中，TUT 4/7和3 p水平上调，而5 p水平降低。链比率的操纵足以损害胶质母细胞瘤细胞增殖。这项研究揭示了尿苷酸化作为分子开关在选择性链选择中的作用，并暗示了其治疗潜力。
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.