Hammell Christopher M
University of Massachusetts Medical School, Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
RNA Biol. 2008 Jul-Sep;5(3):123-7. doi: 10.4161/rna.5.3.6570. Epub 2008 Jul 8.
With the cloning the lin-4 gene in 1993, the possibility of an approximately 21-nucleotide RNA functioning as a regulatory molecule intrigued a relatively small number of scientists. This idea appeared to be a peculiarity of C. elegans as it was not until seven years later that the second, more conserved small RNA, let-7 was cloned. A spate of papers in 2000 and 2001 revealed that the underlying properties of the lin-4 and let-7 genes were a common facet of animal genomes and the absolute number and potential of this new class of gene products requires us to integrate them with other aspects of gene expression and evolution.(1-3) A wealth of information has accumulated in the intervening years that outline, in general, how these small RNAs are expressed and processed into a functional form. Contemporaneous to these studies, experiments also identified a cadre of evolutionarily conserved proteins, the Argonautes (Agos) that directly associate with and are required for microRNA function. Computational and experimental methods have led the identification of many functional mRNA targets. In the last few years, a significant body of work has focused on resolving two key issues: How do microRNAs function in particular genetic contexts (i.e., as "molecular switches" or "fine-tuners" of gene expression) and secondly, what facet/s of mRNA metabolism do microRNAs modulate in their role(s) as a regulatory molecule? The primary objective here is not to comprehensively compare the competing models of microRNA function (reviewed in refs. 4-6) but to frame a potential solution to these two fundamental questions by suggesting that the core microRNA-Ribonucleic-Protein Complex (microRNP), composed of the microRNA and an Ago protein, functions as a highly modifiable scaffold that associates with specific mRNAs via the bound microRNA and facilitates the localized activity of a variety of accessory proteins. The resulting composite mechanism could account for the apparent complexities of measuring microRNA activity and furthermore, accommodate the broad levels of regulation observed in vivo.
1993年随着lin - 4基因的克隆，一种约21个核苷酸的RNA作为调控分子发挥作用的可能性引起了相对少数科学家的兴趣。这个想法似乎是秀丽隐杆线虫的一个特性，因为直到七年后第二个更保守的小RNA——let - 7才被克隆出来。2000年和2001年的一系列论文表明，lin - 4和let - 7基因的潜在特性是动物基因组的一个共同方面，这类新基因产物的绝对数量和潜力要求我们将它们与基因表达和进化的其他方面整合起来。（1 - 3）在这期间积累了大量信息，总体上概述了这些小RNA是如何表达并加工成功能形式的。与这些研究同时进行的是，实验还鉴定出了一批进化上保守的蛋白质，即与微小RNA功能直接相关且必不可少的AGO蛋白。计算和实验方法促成了许多功能性mRNA靶标的鉴定。在过去几年里，大量工作集中在解决两个关键问题：微小RNA在特定遗传背景下如何发挥作用（即作为基因表达的“分子开关”或“微调器”），其次，微小RNA作为调控分子发挥作用时调节了mRNA代谢的哪些方面？这里的主要目的不是全面比较微小RNA功能的相互竞争模型（参考文献4 - 6中有综述），而是通过提出由微小RNA和AGO蛋白组成的核心微小RNA - 核糖核蛋白复合体（微小RNP）作为一个高度可修饰的支架发挥作用，该支架通过结合的微小RNA与特定mRNA结合，并促进多种辅助蛋白的局部活性，来为这两个基本问题构建一个潜在的解决方案。由此产生的复合机制可以解释测量微小RNA活性时明显的复杂性，此外，还能适应体内观察到的广泛调控水平。
