Modulation of microRNA processing by p53
Modulation of microRNA processing by p53
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DOI：
10.1038/nature08199
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发表时间：
2009-07-23
期刊：
影响因子：
64.8
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Suzuki, Hiroshi I.;Yamagata, Kaoru;Miyazono, Kohei
microRNA（miRNAs）是基因表达的关键转录后调节因子，参与多种生理和病理过程。尽管miRNA在肿瘤发展中既可作为肿瘤抑制因子又可作为致癌基因发挥作用（1），但在人类癌症中通常观察到miRNA的广泛下调，并促进细胞转化和肿瘤发生（2-4）。这表明小RNA在肿瘤抑制中的固有意义。然而，肿瘤抑制网络和miRNA生物发生机制之间的联系尚未深入研究。在这里，我们表明，一个中央肿瘤抑制因子，p53，增强了几个miRNA的转录后成熟与生长抑制功能，包括miR-16-1，miR-143和miR-145，在响应DNA损伤。在HCT 116细胞和人二倍体成纤维细胞中，p53通过与DEAD盒RNA解旋酶p68（也称为DDX 5）的结合与Drosha加工复合物相互作用，并促进初级miRNA加工成前体miRNA。我们还发现转录失活的p53突变体干扰Drosha复合物和p68之间的功能组装，导致miRNA加工活性减弱。这些发现表明，miRNA生物发生的转录独立调节本质上嵌入由p53控制的肿瘤抑制程序中。我们的研究揭示了p53在miRNA加工中以前未被认识的功能，这可能是癌症生物学的关键方面。
MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour suppressors and oncogenes in tumour development(1), a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis(2-4). This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between Drosha complex and p68, leading to attenuation of miRNA processing activity. These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.