Thirteen years ago, a genetic screen in Caenorhabditis elegans, established to identify genes involved in developmental timing, resulted in the discovery of the first microRNA (miRNA), lin-4, which at the time was an unprecedented type of small regulatory RNA. After 7 years, the second RNA from this class, let-7, also emerged from a C. elegans genetic screen. The discovery of let-7 was particularly exciting because its phylogenetic conservation in metazoans implied that miRNAs represent a novel conserved regulatory mechanism and this immediately raised the question: how many miRNAs are out there? The discovery of let-7 coincided with an era when genetic and mechanistic studies started to unveil the mechanism of RNA interference, and the connection between the two pathways was soon made. The identification of the structural characteristics of miRNAs initiated the development of efficient cloning strategies that resulted in the isolation of dozens of miRNAs from diverse eukaryotic species. Meanwhile, many genome projects have been completed and the annotated genomes provided platforms to predict miRNAs based on their known features. This significantly extended the number of potential miRNA genes. Today, the miRBase database contains 4039 miRNA entries from 38 species. The large number of verified and predicted miRNAs immediately created a new challenge. What are the functions of miRNAs and what genes do they regulate? Genetic, cell biology and bioinformatics data suggest that miRNAs are key components of a wide range of biological processes, including pathways leading to cancer.
This issue of Oncogene reviews summarizes our recent knowledge about the connection between miRNAs and different aspects of tumorigenesis. The first two papers are dedicated to describing the mechanisms of miRNA production, miRNA processing and miRNA-mediated gene regulation. Zeng (2006) provides an overview of the transcription, nuclear processing and transport of miRNAs from the nucleus to the cytoplasm, where the final maturation steps occur, generating the single-stranded biologically active miRNAs. This review also devotes a section to discuss the differences between animal and plant miRNAs. The next review describes the mechanisms leading to formation of the RNA-induced silencing complex and explains how miRNA machines can regulate gene expression. In addition, it summarizes recent views about the global effects of miRNAs on the transcriptome and their influence on development (Engels and Hutvagner, 2006).
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