Abstract
Micro-RNAs (miRNAs) are a class of non-coding RNAs (ncRNAs) that act as post-transcriptional regulators of gene expression. Since their discovery in 1993, they have been the subject of deep study due to their involvement in many important biological processes. Compared with other ncRNAs, miRNAs are generated from devoted transcriptional units which are processed by a specific set of endonucleases. The contribution of structural biology methods for understanding miRNA biogenesis and function has been essential for the dissection of their roles in cell biology and human disease. In this review, we summarize the application of structural biology for the characterization of the molecular players involved in miRNA biogenesis (processors and effectors), starting from the X-ray crystallography methods to the more recent cryo-electron microscopy protocols.
Highlights
In 1993, the research groups led by Victor Ambros and Gary Ruvkun published two side-by-side papers in the Cell journal, describing the regulatory effects exerted by a tiny RNA discovered in Caenorhabditis elegans [1,2]
These results suggested that the specificity of cleavage by the microprocessor is dependent on the recognition of the apical region of the pri-miRNA by the DGCR8 dimer that will trigger the further assembly and catalysis of the Drosha RNAse [36,37,38]
The nature of the specialized nucleases that process the precursor transcriptional units until the production of mature miRNAs has been subject of detailed functional studies facilitated by the most advanced structural biology techniques during the last two decades
Summary
In 1993, the research groups led by Victor Ambros and Gary Ruvkun published two side-by-side papers in the Cell journal, describing the regulatory effects exerted by a tiny RNA discovered in Caenorhabditis elegans [1,2]. According to the obtained experimental evidence from both groups, a small RNA named lin-4, and expressed following an heterochronic pattern, was characterized as a post-transcriptional regulator of the lin-14 gene. The initial results showed that the regulatory action of lin-4 over lin-14 mRNA was exerted by a direct binding of the ncRNA to the 3 -UTR region of the coding transcript [1,2]. The miRNAs showed a distinctive biogenesis pathway, where specific transcriptional units are processed by a group of defined nucleases to generate the small regulatory RNA [18]. Structural biology has benefit from the rapid development of new methods and from the adaptation and improvement of the already existing ones. We analyzed the highlights of structural biology applied to the field of miRNA biogenesis, showing the evolution of this fascinating field from the first crystal structures of Argonaute proteins isolated from extremophilic bacteria to the more recent high-resolution cryo-EM structures of human nuclear and cytoplasmic miRNA processors
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