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Loscher, M; Schosserer, M; Dausse, E; Lee, K; Ajuh, P; Grillari-Voglauer, R; Lamond, AI; Toulme, JJ; Grillari, J.
(2012): Inhibition of Pre-mRNA Splicing by a Synthetic Blom7 alpha-Interacting Small RNA
PLOS ONE. 2012; 7(10): FullText FullText_BOKU

Abstract:: Originally the novel protein Blom7 alpha was identified as novel pre-mRNA splicing factor that interacts with SNEVPrp19/Pso4, an essential protein involved in extension of human endothelial cell life span, DNA damage repair, the ubiquitin-proteasome system, and pre-mRNA splicing. Blom7 alpha belongs to the heteronuclear ribonucleoprotein K homology (KH) protein family, displaying 2 KH domains, a well conserved and widespread RNA-binding motif. In order to identify specific sequence binding motifs, we here used Systematic Evolution of Ligands by Exponential Enrichment (SELEX) with a synthetic RNA library. Besides sequence motifs like (U/A)(1-4) C2-6 (U/A)(1-5), we identified an AC-rich RNA-aptamer that we termed AK48 (Aptamer KH-binding 48), binding to Blom7 alpha with high affinity. Addition of AK48 to pre-mRNA splicing reactions in vitro inhibited the formation of mature spliced mRNA and led to a slight accumulation of the H complex of the spliceosome. These results suggest that the RNA binding activity of Blom7 alpha might be required for pre-mRNA splicing catalysis. The inhibition of in-vitro splicing by the small RNA AK48 indicates the potential use of small RNA molecules in targeting the spliceosome complex as a novel target for drug development.
Authors BOKU Wien:: Grillari Johannes; Grillari Regina; Schosserer Markus
Find related publications in this database (using NML MeSH Indexing): AT Rich Sequence/genetics;Amino Acid Sequence;Aptamers, Nucleotide/genetics;Aptamers, Nucleotide/metabolism*;Aptamers, Nucleotide/pharmacology;Base Sequence;Binding Sites/genetics;Electrophoretic Mobility Shift Assay;HeLa Cells;Heterogeneous-Nuclear Ribonucleoprotein K/genetics;Heterogeneous-Nuclear Ribonucleoprotein K/metabolism*;Heterogeneous-Nuclear Ribonucleoproteins/genetics;Heterogeneous-Nuclear Ribonucleoproteins/metabolism*;Humans;Molecular Sequence Data;Mutation;Protein Binding;RNA Precursors/genetics;RNA Precursors/metabolism*;RNA Splicing*;SELEX Aptamer Technique/methods;Sequence Homology, Amino Acid;Spliceosomes/drug effects;Spliceosomes/genetics;Spliceosomes/metabolism;