Paper 2: Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing
microRNAs (miRNAs) are thought to play an important role in the posttranscriptional gene regulation of up to 30% of all human genes [1]. The updated version (V.17) of the miRNA database miRBase currently distinguishes 1424 different human miRNA sequences
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Paper 2: Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1 and TARBP2 in epithelial skin cancer *
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Introduction
microRNAs (miRNAs) are thought to play an important role in the posttranscriptional gene regulation of up to 30% of all human genes [1]. The updated version (V.17) of the miRNA database miRBase currently distinguishes 1424 different human miRNA sequences [2]. miRNAs are capable of regulating gene expression both by promoting mRNA degradation and by inhibiting mRNA translation [3]. The maturation of miRNAs occurs in the nucleus and the cytoplasm. The process begins in the nucleus, where the intranuclear enzyme Drosha, an RNase III endonuclease, cleaves pri-miRNAs (consisting of a hairpin stem, a terminal loop, and 5` and 3` single-stranded RNA extensions) to premiRNAs (60-70 nucleotide stem-loop structures). In addition to Drosha, the DiGeorge syndrome critical region gene 8 (DGCR8 or Pasha), which is the product of a gene deleted in DiGeorge syndrome, is also part of the miRNA maturing microprocessor complex and has been shown to be essential for miRNA maturation [4]. While Drosha functions as the catalytic subunit of the microprocessor complex, DGCR8 stabilizes Drosha through protein-protein interactions and is responsible for recognition of the RNA substrate [5,6]. The resulting pre-miRNAs are transported into the cytoplasm by Exportin 5 [7]. Here, Dicer, another RNase III enzyme, cleaves the pre-miNAs into mature miRNAs [8]. The intracellular effects of miRNAs are achieved by the RNA-induced silencing complex (RISC), a 200- to 500-kDa multiprotein effector complex with endonuclease activity, which integrates mature miRNA strands. The incorporated miRNA guides the RISC to its specific mRNA *
Co-authors: Marina Skrygan Ph.D., Christoph Arenz Ph.D., Dimitrios Georgas M.D., Thilo Gambichler M.D., Daniel Sand M.D., Peter Altmeyer M.D., Falk G. Bechara M.D.
© Springer Fachmedien Wiesbaden 2016 M. Sand, MicroRNAs in malignant tumors of the skin, DOI 10.1007/978-3-658-12794-7_6
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target through base-pair complementation. Once the miRNA has annealed to the target mRNA (near-perfect hybridization), the RISC disrupts translation by cleaving the target mRNA [9]. Weaker hybridization leads to translational repression or degradation of the mRNA [10]. The RISC is the central element of the RNA silencing pathway and consists of several different proteins that comprise a multiprotein complex. The best-characterized RISC proteins include the methyltransferase TARBP1 (TAR [HIV-1] RNA binding protein), the RISC-loading complex subunit TARBP2 (TAR [HIV-1] RNA binding protein), the RISC core components argonaute-1 (AGO1, eukaryotic translation initiation factor 2C.1, EIF2C1) and argonaute-2 (AGO2, eukaryotic translation initiation factor 2C.2, EIF2C2) and the dsRNAbinding protein PACT. TARBPs are double-stranded RNA binding proteins (dsRBP) that load short RNAs into the RISC [
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