TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation
TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation
复制标题
DOI：
10.1016/j.cell.2009.08.002
复制
发表时间：
2009-08-21
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;Joo, Chirlmin;Kim, V. Narry
作为细胞功能的关键调节因子，微小RNA（miRNA）自身需要受到严格调控。据报道，多能性因子Lin28通过诱导let - 7 miRNA前体（pre - let - 7）的尿苷化来下调let - 7 miRNA，但负责尿苷化的酶一直未知。在此我们确定一种非经典的多聚（A）聚合酶，TUTase4（TUT4），为pre - let - 7的尿苷酰转移酶。Lin28通过识别末端环中的一个四核苷酸序列基序（GGAG）将TUT4招募至pre - let - 7。反过来，TUT4给pre - let - 7添加一个寡聚尿苷尾，这会阻断Dicer加工。具有相同序列基序的其他miRNA（miR - 107、 - 143和 - 200c）通过相同机制受到调控。TUT4和Lin28的敲低会降低干细胞标志物的水平，表明它们是干细胞维持所必需的。这项研究揭示了TUT4和Lin28作为miRNA生物发生的特异性抑制因子的作用，这对干细胞研究和癌症生物学具有重要意义。
As key regulators in cellular functions, microRNAs (miRNAs) themselves need to be tightly controlled. Lin28, a pluripotency factor, was reported to downregulate let-7 miRNA by inducing uridylation of let-7 precursor (pre-let-7). But the enzyme responsible for the uridylation remained unknown. Here we identify a noncanonical poly (A) polymerase, TUTase4 (TUT4), as the uridylyl transferase for pre-let-7. Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop. TUT4 in turn adds an oligouridine tail to the pre-let-7, which blocks Dicer processing. Other miRNAs with the same sequence motif (miR-107, -143, and -200c) are regulated through the same mechanism. Knockdown of TUT4 and Lin28 reduces the level of stem cell markers, suggesting that they are required for stem cell maintenance. This study uncovers the role of TUT4 and Lin28 as specific suppressors of miRNA biogenesis, which has implications for stem cell research and cancer biology.