女科学家再发《Cell》microRNA自我调节机制

　　

生物通报道，韩国首尔国立大学生物科学与创新性研究中心的科学家在microRNA自我调节功能的研究上取得最新的进展，相关成果文章TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation发表在最新的Cell杂志上。

 

文章通讯作者是韩国顶级女科学家V. Narry Kim，在RNAi领域颇有建树，2008年曾在Cell上发表microRNA分类文章的介绍（Cell, 133, 25 – 26, April 4, 2008）。

 

microRNA是调节细胞功能的关键因子，除了对细胞功能有重要的调节作用外，microRNA自身也需要被严格地调控，方能发挥应有的作用。Lin28，一种多功能因子，被报道具有下调let-7 miRNA的功能，Lin28介导Let-7前体的末端尿苷化，从而阻断了Dicer的处理过程及let-7的成熟。

 

但是这个过程的分子机制目前尚不清楚。在本研究中，作者通过RNA亲和纯化和免疫共沉淀这些普通的实验室技术， 阐明了一种不常见的Poly(A)多聚酶-TUT4，该酶在Lin-28的参与下，结合到 pre-let-7尚而阻断其成熟。

 

 体外试验发现，TUT4在Lin28帮助下，可以对 pre-let-7进行尿苷化。敲除了TUT4的鼠胚胎干细胞let-7表达水平上升，最终失去了多能性。作者发现这种交互作用发生于GGAG基序，该基序存在于pre-let-7的环部。其它带有此基序的miRNA前体，也可经 Lin28/TUT4 途径而得以尿苷化。

 

这一研究结果，对干细胞和癌症生物学研究有很重要的意义。

（生物通 小茜）

生物通推荐原文检索

TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation

Inha Heo1, 2, Chirlmin Joo1, 2, Young-Kook Kim1, 2, Minju Ha1, Mi-Jeong Yoon1, Jun Cho1, Kyu-Hyeon Yeom1, Jinju Han1 and V. Narry Kim1, , 

 

1 Creative Research Center and School of Biological Sciences, Seoul National University, Seoul, Korea 151-742

 

Corresponding author

2 These authors contributed equally to this work

 

【Summary】

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.