A role of uridylation pathway for blockade of let-7 microRNA biogenesis by Lin28B.
A role of uridylation pathway for blockade of let-7 microRNA biogenesis by Lin28B.
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DOI：
10.1111/cas.12721
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发表时间：
2015-09
期刊：
影响因子：
5.7
通讯作者：
Miyazono K
中科院分区：
文献类型：
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作者：
Suzuki HI;Katsura A;Miyazono K
对microRNA(MiRNA)生物合成的精确控制是基因调控的关键。Lin28a和Lin28b是参与发育和肿瘤发生的let-7 miRNAs生物发生的选择性抑制物。LIN28a通过TUT4末端尿苷转移酶对前体LET-7的胞质尿苷化和Dis312核酸外切酶的降解，选择性地抑制LET-7的生物发生。然而，这种尿苷酸化途径在Lin28a的类似基因Lin28b阻断let-7中的作用尚不清楚，而Lin28b被报道在细胞核中参与了一种不同的机制来抑制let-7。在这里，我们回顾了Lin28b和尿酸化途径之间的功能联系，重点是癌细胞中let-7的代谢。在表达Lin28a和Lin28b的癌细胞中，Lin28a和Lin28b都与Dis3l2在细胞质中相互作用，而Dis3l2的沉默上调了尿苷化的Pre-let-7。此外，我们还发现，LET-7前体的数量影响Lin28b的细胞内定位。此外，我们还发现MCPIP1(Zc3h12a)核糖核酸酶也参与了非尿苷化和尿苷化Pre-let-7的降解。肿瘤转录组分析表明，Lin28b的表达水平与尿苷途径组分TUT4和Dis3l2在不同的人类癌细胞和肝细胞癌中存在关联。综上所述，这些结果表明胞质尿苷基化途径积极参与了Lin28b对let-7生物发生的阻断。
The precise control of microRNA (miRNA) biosynthesis is crucial for gene regulation. Lin28A and Lin28B are selective inhibitors of biogenesis of let-7 miRNAs involved in development and tumorigenesis. Lin28A selectively inhibits let-7 biogenesis through cytoplasmic uridylation of precursor let-7 by TUT4 terminal uridyl transferase and subsequent degradation by Dis3l2 exonuclease. However, a role of this uridylation pathway remains unclear in let-7 blockade by Lin28B, a paralog of Lin28A, while Lin28B is reported to engage a distinct mechanism in the nucleus to suppress let-7. Here we revisit a functional link between Lin28B and the uridylation pathway with a focus on let-7 metabolism in cancer cells. Both Lin28A and Lin28B interacted with Dis3l2 in the cytoplasm, and silencing of Dis3l2 upregulated uridylated pre-let-7 in both Lin28A- and Lin28B-expressing cancer cell lines. In addition, we found that amounts of let-7 precursors influenced intracellular localization of Lin28B. Furthermore, we found that MCPIP1 (Zc3h12a) ribonuclease was also involved in degradation of both non-uridylated and uridylated pre-let-7. Cancer transcriptome analysis showed association of expression levels of Lin28B and uridylation pathway components, TUT4 and Dis3l2, in various human cancer cells and hepatocellular carcinoma. Collectively, these results suggest that cytoplasmic uridylation pathway actively participates in blockade of let-7 biogenesis by Lin28B.