Mono-Uridylation of Pre-MicroRNA as a Key Step in the Biogenesis of Group II let-7 MicroRNAs
Mono-Uridylation of Pre-MicroRNA as a Key Step in the Biogenesis of Group II let-7 MicroRNAs
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DOI：
10.1016/j.cell.2012.09.022
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发表时间：
2012-10-26
期刊：
影响因子：
64.5
通讯作者：
Kim, V. Narry
中科院分区：
文献类型：
--
作者：
Heo, Inha;Ha, Minju;Kim, V. Narry
RNase III Drosha通过切割初级miRNA转录物并释放具有2nt 3'突出端的pre-miRNA来启动microRNA（miRNA）成熟。Dicer识别2nt的3'突出端结构以选择性地加工pre-miRNA。在此，我们发现，与原型pre-miRNA（组I）不同，组II pre-miRNA从Drosha加工获得较短的（1 nt）3'突出端，因此需要3'末端单尿苷酸化用于Dicer加工。大多数let-7和miR-105属于II组。我们鉴定TUT 7/ZCCHC 6、TUT 4/ZCCHC 11和TUT 2/PAPD 4/GLD 2为负责前体miRNA单尿苷酸化的末端尿苷酰转移酶。TUT特异性作用于具有Int 3'突出端的dsRNA，从而产生2nt 3'突出端。TUT的消耗降低let-7水平并破坏let-7功能。尽管let-7抑制因子Lin 28在胚胎干细胞中诱导抑制性寡尿苷酸化，但在缺乏Lin 28的体细胞中发生单尿苷酸化以促进let-7生物发生。我们的研究揭示了尿苷酸化的功能双重性，并介绍了TUT 7/4/2作为miRNA生物合成途径的组成部分。
RNase III Drosha initiates microRNA (miRNA) maturation by cleaving a primary miRNA transcript and releasing a pre-miRNA with a 2 nt 3' overhang. Dicer recognizes the 2 nt 3' overhang structure to selectively process pre-miRNAs. Here, we find that, unlike prototypic pre-miRNAs (group I), group II pre-miRNAs acquire a shorter (1 nt) 3' overhang from Drosha processing and therefore require a 3'-end mono-uridylation for Dicer processing. The majority of let-7 and miR-105 belong to group II. We identify TUT7/ZCCHC6, TUT4/ZCCHC11, and TUT2/PAPD4/GLD2 as the terminal uridylyl transferases responsible for pre-miRNA mono-uridylation. The TUTs act specifically on dsRNAs with a 1 nt 3' overhang, thereby creating a 2 nt 3' overhang. Depletion of TUTs reduces let-7 levels and disrupts let-7 function. Although the let-7 suppressor, Lin28, induces inhibitory oligo-uridylation in embryonic stem cells, mono-uridylation occurs in somatic cells lacking Lin28 to promote let-7 biogenesis. Our study reveals functional duality of uridylation and introduces TUT7/4/2 as components of the miRNA biogenesis pathway.