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Jonas Hönig, Ivana Mižíková, Claudio Nardiello, David Emanuel Surate Solaligue, Maximilian J Daume, István Vadász, Konstantin Mayer, Susanne Herold, Stefan Günther, Werner Seeger, Rory Edward Morty
The emergence of microRNA as regulators of organogenesis and tissue differentiation has stimulated interest in the ablation of microRNA expression and function during discrete periods of development. To this end, inducible, conditional modulation of microRNA expression with doxycycline-based tetracycline-controlled transactivator and tamoxifen-based estrogen receptor systems has found widespread use. However, the induction agents and components of genome recombination systems negatively impact pregnancy, parturition, and post natal development; thereby limiting the use of these technologies between late gestation and the early post-natal period...
March 14, 2018: RNA
Junjie Luo, Yirong Wang, Jian Yuan, Zhilei Zhao, Jian Lu
The repertoire of miRNAs has considerably expanded during metazoan evolution, and duplication is an important mechanism for generating new functional miRNAs. However, relatively little is known about the functional divergence between paralogous miRNAs and the possible co-evolution between duplicated miRNAs and the genomic contexts. By systematically examining small RNA expression profiles across various human tissues and interrogating the publicly available miRNA:mRNA pairing chimeras, we found that changes in expression patterns and targeting preferences are widespread for duplicated miRNAs in vertebrates...
March 6, 2018: RNA
Andrew J MacRae, Megan Mayerle, Eva Hrabeta-Robinson, Robert J Chalkley, Christine Guthrie, A L Burlingame, Melissa Jurica
Prp8 is an essential protein that regulates spliceosome assembly and conformation during pre-mRNA splicing. Recent cryo-EM structures of the spliceosome model Prp8 as scaffolding the spliceosome's catalytic U snRNA components. Using a new amino acid probing strategy, we identified a dynamic region in human Prp8 that is positioned to stabilize the pre-mRNA in the spliceosome active site through interactions with U5 snRNA. Mutagenesis of the identified Prp8 residues in yeast indicates a role in 5' splice site recognition...
February 27, 2018: RNA
Renata Grzela, Karolina Nasilowska, Maciej Lukaszewicz, Michal Tyras, Janusz Stepinski, Marzena Jankowska-Anyszka, Elzbieta Bojarska, Edward Darzynkiewicz
Human Nudt16 (hNudt16) is a member of the Nudix family of hydrolases comprising enzymes catabolizing various substrates including canonical (d)NTPs, oxidized (d)NTPs, non-nucleoside polyphosphates, and capped mRNAs. Decapping activity of the Xenopus laevis (X29) Nudt16 homolog was observed in the nucleolus, with a high specificity towards U8 snoRNA. Subsequent studies have reported cytoplasmic localization of mammalian Nudt16 with cap hydrolysis activity initiating RNA turnover, similar to Dcp2. The present study focuses on hNudt16 and its hydrolytic activity towards dinucleotide cap analogs and short capped oligonucleotides...
February 26, 2018: RNA
Kalevi Trontti, Juho Väänänen, Tessa Sipilä, Dario Greco, Iiris Hovatta
Diversity in the structure and expression of microRNAs, important regulators of gene expression, arises from SNPs, duplications followed by divergence, production of isomiRs, and RNA editing. Inbred mouse strains and crosses using them are important reference populations for genetic mapping, and as models of human disease. We determined the nature and extent of interstrain miRNA variation by 1) identifying miRNA SNPs in whole genome sequence data from 36 strains, and 2) examining miRNA editing and expression in hippocampus (Hpc) and frontal cortex (FCx) of 6 strains, to facilitate the study of miRNAs in neurobehavioral phenotypes...
February 14, 2018: RNA
Chia-Lung Li, Wei-Zen Yang, Zhonghao Shi, Hanna S Yuan
Tudor staphylococcal nuclease (TSN) is an evolutionarily conserved ribonuclease in eukaryotes that is composed of five staphylococcal nuclease-like domains (SN1 to SN5) and a Tudor domain. TSN degrades hyper-edited double-stranded RNA, including primary miRNA precursors containing multiple I-U and U-I pairs, and mature miRNA during miRNA decay. However, how TSN binds and degrades its RNA substrates remains unclear. Here, we show that the C. elegans TSN (cTSN) is a monomeric Ca2+ -dependent ribonuclease, cleaving RNA chains at the 5'-side of the phosphodiester linkage to produce degraded fragments with 5'-hydroxyl and 3'-phosphate ends...
February 13, 2018: RNA
Jenna M Lentini, Jillian Ramos, Dragony Fu
The post-transcriptional modification of tRNA at the wobble position is a universal process occurring in all domains of life. In eukaryotes, the wobble uridine of particular tRNAs is transformed to the 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) modification which is critical for proper mRNA decoding and protein translation. However, current methods to detect mcm5s2U are technically challenging and/or require specialized instrumental expertise. Here, we show that gamma-toxin endonuclease from the yeast Kluyveromyces lactis can be used as a probe for assaying mcm5s2U status in the tRNA of diverse eukaryotic organisms ranging from protozoans to mammalian cells...
February 13, 2018: RNA
Emily L Gulliver, Amy Wright, Deanna Deveson Lucas, Marianne Mégroz, Oded Kleifeld, Ralf Schittenhelm, David Powell, Torsten Seemann, Juergen Bulitta, Marina Harper, John D Boyce
Pasteurella multocida is a Gram-negative bacterium responsible for many important animal diseases. While a number of P. multocida virulence factors have been identified, very little is known about how gene expression and protein production is regulated in this organism. Small RNA (sRNA) molecules are critical regulators that act by binding to specific mRNA targets, often in association with the RNA chaperone protein Hfq. In this study, transcriptomic analysis of the P. multocida strain VP161 revealed a putative sRNA with high identity to GcvB from Escherichia coli and Salmonella enterica serovar Typhimurium...
February 12, 2018: RNA
Monica C Pillon, Mack Sobhanhy, Robin E Stanley
Grc3 is an essential well-conserved eukaryotic polynucleotide kinase (PNK) that cooperates with the endoribonuclease Las1 to process the pre-ribosomal RNA (rRNA). Aside from being dependent upon Las1 for coordinated kinase and nuclease function, little is known about Grc3 substrate specificity and the molecular mechanisms governing kinase activity. Here we characterize the kinase activity of Grc3 and identify key similarities and differences between Grc3 and other polynucleotide kinase family members. In contrast to other PNK family members, Grc3 has distinct substrate preferences for RNA substrates in vitro...
February 9, 2018: RNA
Andrew Lugowski, Beth Nicholson, Olivia Selfridge Rissland
Control of messenger RNA (mRNA) stability is an important aspect of gene regulation. The gold standard for measuring mRNA stability transcriptome-wide uses metabolic labeling, biochemical isolation of labeled RNA populations, and high-throughput sequencing. However, difficult normalization procedures have inhibited widespread adoption of this approach. Here, we present DRUID (for Determination of Rates Using Intron Dynamics), a new computational pipeline that is robust, easy to use, and freely available. Our pipeline uses endogenous introns to normalize time course data and yields reproducible half-lives, even with datasets that were otherwise unusable...
February 8, 2018: RNA
Jack C-C Hsu, David W Reid, Alyson M Hoffman, Devanand Sarkar, Christopher V Nicchitta
Astrocyte elevated gene-1 (AEG-1), an oncogene whose overexpression promotes tumor cell proliferation, angiogenesis, invasion, and enhanced chemoresistance, is thought to function primarily as a scaffolding protein, regulating PI3K/Akt and Wnt/β-catenin signaling pathways. Here we report that AEG-1 is an endoplasmic reticulum (ER) resident integral membrane RNA-binding protein (RBP). Examination of the AEG-1 RNA interactome by HITS-CLIP and PAR-CLIP methodologies revealed a high enrichment for endomembrane organelle-encoding transcripts, most prominently those encoding ER resident proteins, and within this cohort, for integral membrane protein-encoding RNAs...
February 7, 2018: RNA
Aleksandar Spasic, Scott D Kennedy, Laura Needham, Muthiah Manoharan, Ryszard Kierzek, Douglas H Turner, David Mathews
The RNA "GAGU" duplex, (5'GACGAGUGUCA)2, contains the internal loop (5'-GAGU-3')2 , which has two conformations in solution as determined by NMR spectroscopy. The major conformation has a loop structure consisting of trans-Watson-Crick/Hoogsteen GG pairs, two A residues stacked on each other, two U residues bulged outside the helix and exposed to solvent, and all sugars with a C2'-endo conformation. This differs markedly from the internal loops, (5'-GAGC-3')2 , (5'-AAGU-3')2 and (5'-UAGG-3')2, which all have cis-Watson-Crick/Watson-Crick AG "imino" non-canonical pairs flanked by cis Watson-Crick/Watson-Crick canonical pairs resulting in maximal hydrogen bonding...
February 6, 2018: RNA
Marcus Davidsson, Paula Díaz-Fernández, Marcos Torroba, Oliver D Schwich, Patrick Aldrin-Kirk, Luis Quintino, Andreas Heuer, Gang Wang, Cecilia Lundberg, Tomas Bjorklund
Genome editing has proven to be highly potent in the generation of functional gene knockouts in dividing cells. In the CNS however, efficient technologies to repair sequences are yet to materialize. Reprogramming on the mRNA level is an attractive alternative as it provides means to perform in situ editing of coding sequences without nuclease dependency. Furthermore, de novo sequences can be inserted without the requirement of homologous recombination. Such reprogramming would enable efficient editing in quiescent cells (e...
January 31, 2018: RNA
Allison L Didychuk, Samuel E Butcher, David A Brow
Removal of introns from precursor messenger RNA (pre-mRNA) and some non-coding transcripts is an essential step in eukaryotic gene expression. In the nucleus, this process of RNA splicing is carried out by the spliceosome, a multi-megaDalton macromolecular machine whose core components are conserved from yeast to humans. In addition to many proteins, the spliceosome contains five uridine-rich small nuclear RNAs (snRNAs) that undergo an elaborate series of conformational changes to correctly recognize the splice sites and catalyze intron removal...
January 24, 2018: RNA
Pavel V Mazin, Xi Jiang, Ning Fu, Dingding Han, Meng Guo, Mikhail S Gelfand, Philipp Khaitovich
Changes in splicing are known to affect the function and regulation of genes. We analyzed splicing events that take place during the postnatal development of the prefrontal cortex in humans, chimpanzees, and rhesus macaques based on data obtained from 168 individuals. Our study revealed that among the 38,822 quantified alternative exons, 15% are differentially spliced among species, and more than 6% splice differently at different age. Mutations in splicing acceptor and/or donor sites might explain more than 14% of all splicing differences among species and up to 64% of high-amplitude differences...
January 23, 2018: RNA
Natalia Akulenko, Sergei Ryazansky, Valeriya Morgunova, Pavel A Komarov, Ivan Olovnikov, Chantal Vaury, Silke Jensen, Alla Kalmykova
Expression of transposable elements in the germline is controlled by Piwi-interacting (pi) RNAs produced by genomic loci termed piRNA clusters and associated with Rhino, a Heterochromatin Protein 1 (HP1) homolog. Previously, we have shown that transgenes containing a fragment of the I retrotransposon form de novo piRNA clusters in the Drosophila germline providing suppression of I-element activity. We noted that identical transgenes located in different genomic sites vary considerably in piRNA production and classified them as "strong" and "weak" piRNA clusters...
January 22, 2018: RNA
Ester Saus, Jesse R Willis, Leszek P Pryszcz, Ahmed Hafez, Carlos Llorens, Heinz Himmelbauer, Toni Gabaldón
RNA molecules play important roles in virtually every cellular process. These functions are often mediated through the adoption of specific structures that enable RNAs to interact with other molecules. Thus, determining the secondary structures of RNAs is central to understanding their function and evolution. In recent years several sequencing-based approaches have been developed that allow probing structural features of thousands of RNA molecules present in a sample. Here, we describe nextPARS, a novel Illumina-based implementation of in-vitro parallel probing of RNA structures...
January 22, 2018: RNA
Yusuke Matsumoto, Keisuke Ohta, Daniel Kolakofsky, Machiko Nishio
The unusual ability of a human parainfluenza virus type 2 (hPIV2) nucleoprotein point mutation (NPQ202A) to strongly enhance minigenome replication was found to depend on the absence of a functional, internal element of the bipartite replication promoter (CRII). This point mutation allows relatively robust CRII-minus minigenome replication in a CRII-independent manner, under conditions in which NPwt is essentially inactive. The nature of the aa at position 202 apparently controls whether viral RNA-dependent RNA polymerase (vRdRp) can, or cannot, initiate RNA synthesis in a CRII-independent manner...
January 22, 2018: RNA
Eva Schöller, Franziska Weichmann, Thomas Treiber, Sam Ringle, Nora Treiber, Andrew Flatley, Regina Feederle, Astrid Bruckmann, Gunter Meister
N6-methyladenine (m6A) is found on many eukaryotic RNAs including mRNAs. M6A modification has been implicated in mRNA stability and turn over, localization or translation efficiency. A heterodimeric enzyme complex composed of METTL3 and METTL14 generates m6A on mRNAs. METTL3/14 is found in the nucleus where it is localized to nuclear speckles and the splicing regulator WTAP is required for this distinct nuclear localization pattern. Although recent crystal structures revealed how the catalytic MT-A70 domains of METTL3 and METTL14 interact with each other, a more global architecture including WTAP and RNA interactions has not been reported so far...
January 18, 2018: RNA
Pamela Nicholson, Asimina Gkratsou, Christoph Josi, Martino Colombo, Oliver Mühlemann
The term "nonsense-mediated mRNA decay" (NMD) originally described the degradation of mRNAs with premature translation-termination codons (PTCs), but its meaning has recently been extended to be a translation-dependent post-transcriptional regulator of gene expression affecting 3-10 % of all mRNAs. The degradation of NMD target mRNAs involves both exonucleolytic and endonucleolytic pathways in mammalian cells. While the latter is mediated by the endonuclease SMG6, the former pathway has been reported to require a complex of SMG5-SMG7 or SMG5-PNRC2 binding to UPF1...
January 18, 2018: RNA
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