MiRNAs in Malignant Melanoma
MicroRNAs (miRNAs) represent a class of small noncoding RNAs, first described in the nematode Caenorhabditis elegans. In 1993, the labs of Victor Ambros (Lee et al. Cell 75:843–854, 1993) and Gary Ruvkun (Wightman et al. Cell 75:855–862, 1993) discovered
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MiRNAs in Malignant Melanoma Maria Mione, Janika Liebig, Leonel Munoz, and Anja Bosserhoff
6.1
MiRNA Biogenesis and Function
6.1.1 T ranscription of miRNA Genes and Processing in the Nucleus MicroRNA genes are embedded in intergenic as well as intragenic regions of the human genome, encoding either a single miRNA species or a cluster of multiple miRNAs in a polycistronic manner (Lee et al. 2002). In the first step of miRNA expression, miRNA genes are transcribed into pri-miRNAs (primary miRNA transcripts; Fig. 6.1). In most cases, transcription is accomplished by RNA polymerase II, resulting in 5′-methyl-guanosine capped and polyadenylated pri-miRNAs, which contain local stem-loop structures and are up to several kilobases in length (Cai et al. 2004; Lee et al. 2004). Some specific miRNAs are initially transcribed by RNA polymerase III (Borchert et al. 2006). While still in the nucleus, the pri- miRNA is endonucleolytically cleaved by the so-called microprocessor complex composed of the RNAse III enzyme Drosha (RNASEN) and its co-factor DGCR8 [DiGeorge syndrome critical region on chromosome 8; Maria Mione, Janika Liebig and Leonel Munoz contributed equally M. Mione ITG, Karlsruhe Institute of Technology, Eggestein-Leopoldshafen, Germany, and Cibio University of Trento, Trento, Italy J. Liebig • A. Bosserhoff (*) Institute of Biochemistry (Emil-Fischer-Zentrum), University of Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany e-mail: [email protected] L. Munoz ITG, Karlsruhe Institute of Technology, Eggestein-Leopoldshafen, Germany, and University of Valparaiso, Karlsruhe, Chile © Springer International Publishing AG 2017 A. Bosserhoff (ed.), Melanoma Development, DOI 10.1007/978-3-319-41319-8_6
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Fig. 6.1 Schematic overview of miRNA biogenesis and function. Please refer to Sect. 6.1 for detailed explanations on the molecular mechanisms involved in each step
also known as Pasha (Partner of Drosha) in Drosophila melanogaster and C. elegans] (Landthaler et al. 2004; Lee et al. 2003). DGCR8 interacts with the ~33 bp stem-loop as well as with the adjacent unpaired flanking regions within the pri-miRNA, thus supporting Drosha-mediated cleavage in the stem region, about 11 bp away from the junction of ssRNA (single-stranded RNA) to dsRNA (double-stranded RNA) (Han et al. 2006; Zeng and Cullen 2005). The resulting pre-miRNA (~70 bp in length) is rapidly translocated to the cytoplasm via the Ran-GTP-dependent nuclear export factor exportin 5 (XPO5), a member of the nuclear transport receptor family (Kim 2004). Export of only correctly processed pre-miRNAs is ensured by recognition of the >14 bp dsRNA stem together with a short (1–8 nucleotides) 3′ overhang (Zeng and Cullen 2003). Exceptions to this rule have been reported, as in the case of cell adhesion complexes sequestering microprocessor components for the localized production of mature miRNAs from nuclear-exported pri-miRNAs (Kourtidis et al. 2015). Interestingly, a number of pre-miRNAs can be exported from the nucleus wit
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