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Michael Yarus
We examine the initial emergence of genetics; that is, of an inherited chemical capability. The crucial actors are ribonucleotides, occasionally meeting in a prebiotic landscape. Previous work identified six influential variables during such random ribonucleotide pooling. Geochemical pools can be in periodic danger (e.g., from tides) or constant danger (e.g., from unfavorable weather). Such pools receive Gaussian nucleotide amounts sporadically, at random times, or get varying substrates simultaneously. Pools use cross-templated RNA synthesis (5'-5' product from 5'-3' template) or para-templated (5'-5' product from 5'-5' template) synthesis...
May 21, 2018: RNA
Nancy Laterreur, Bruno Lemieux, Hannah Neumann, Jean-Christophe Berger-Dancause, Daniel Lafontaine, Raymund J Wellinger
Telomerases are ribonucleoprotein (RNP) enzymes that are related to reverse transcriptases. While they maintain genome stability, their composition varies significantly between species. Yeast telomerase RNPs contain an RNA that is comparatively large and its overall folding shows long helical segments with distal functional parts. Here we investigated the essential stem IVc module of the budding yeast telomerase RNA, called Tlc1. The distal part of stem IVc includes a conserved sequence element CS2a and structurally conserved features to which bind the Pop1/Pop6/Pop7 proteins and which together function analogously to the P3 domains of the RNase P/MRP RNPs...
May 18, 2018: RNA
Tucker Joe Carrocci, Joshua Clark Paulson, Aaron Andrew Hoskins
SF3b1 is an essential component of the U2 snRNP implicated in branch site (BS) recognition and found to be frequently mutated in several human cancers. While recent structures of yeast and human SF3b1 have revealed its molecular architecture, the importance of specific RNA:protein contacts and conformational changes remain largely uncharacterized. Here, we performed mutational analysis of yeast SF3b1, guided by recent structures of the spliceosome. We find that conserved amino acids contacting the U2 snRNA backbone of the U2/BS duplex are nonessential, and that yeast can tolerate truncation of the HEAT repeats containing these amino acids...
May 11, 2018: RNA
Avital Steiman-Shimony, Orr Shtrikman, Hanah Margalit
In human, nearly half of the known microRNAs (miRNAs) are encoded within the introns of protein-coding genes. The embedment of these miRNA genes within the sequences of protein-coding genes alludes to a possible functional relationship between intronic miRNAs and their hosting genes. Several studies, using predicted targets, suggested that intronic miRNAs influence their hosts' function either antagonistically or synergistically. New experimental data of miRNA expression patterns and targets enable exploring this putative association by relying on actual data rather than on predictions...
May 11, 2018: RNA
Sydney P Thomas, Trish T Hoang, Valerie T Ressler, Ronald T Raines
Angiogenin (ANG) is a secretory ribonuclease that promotes the proliferation of endothelial cells, leading to angiogenesis. This function relies on its ribonucleolytic activity, which is low for simple RNA substrates. Upon entry into the cytosol, ANG is sequestered by the ribonuclease inhibitor protein (RNH1). We find that ANG is a potent cytotoxin for RNH1 -knockout HeLa cells, belying its inefficiency as a nonspecific catalyst. The toxicity does, however, rely on the ribonucleolytic activity of ANG and a cytosolic localization, which lead to the accumulation of particular tRNA fragments (tRFs), such as tRF-5 Gly-GCC...
May 10, 2018: RNA
Sarah E Fritz, Nazmul Haque, J Robert Hogg
Cell-free systems are widely used to study mechanisms and regulation of translation, but the use of in vitro transcribed (IVT) mRNAs as translation substrates limits their efficiency and utility. Here, we present an approach for in vitro translation of messenger ribonucleoprotein (mRNP) complexes affinity purified in association with tagged mRNAs expressed in mammalian cells. We show that in vitro translation of purified mRNPs is much more efficient than that achieved using standard IVT mRNA substrates and is compatible with physiological ionic conditions...
May 3, 2018: RNA
Jessica S Kurata, Ren-Jang Lin
MicroRNAs (miRNAs) are posttranscriptional gene regulators that play important roles in the control of cell fitness, differentiation, and development. The CRISPR-Cas9 gene-editing system is composed of the Cas9 nuclease in complex with a single guide RNA (sgRNA) and directs DNA cleavage at a predetermined site. Several CRISPR-Cas9 libraries have been constructed for genome-scale knockout screens of protein function; however few libraries have included miRNA genes. Here we constructed a miRNA-focused CRISPR-Cas9 library that targets 1,594 (85%) annotated human miRNA stem-loops...
May 2, 2018: RNA
Malik Chaker-Margot
The eukaryotic ribosome is made of 4 intricately folded ribosomal RNAs and 79 proteins. During rapid growth, yeast cells produce an incredible 2000 ribosomes every minute. Ribosome assembly involves more than 200 trans-acting factors, intervening from the transcription of the pre-ribosomal RNA in the nucleolus to late maturation events in the cytoplasm. The biogenesis of the small ribosomal subunit, or 40S, is especially intricate, requiring more than 4 times the mass of the small subunit in assembly factors for its full maturation...
April 30, 2018: RNA
Vincent Boivin, Gabrielle Deschamps-Francoeur, Sonia Couture, Ryan Nottingham, Philia Bouchard-Bourelle, Alan M Lambowitz, Michelle S Scott, Sherif Abou Elela
Comparing the abundance of one RNA molecule to another is crucial for understanding cellular functions but most sequencing techniques can target only specific subsets of RNA. In this study, we used a new fragmented ribodepleted TGIRT sequencing method that employs a thermostable group II intron reverse transcriptase (TGIRT) to generate a portrait of the human transcriptome depicting the quantitative relationship of all classes of non-ribosomal RNA longer than sixty nucleotides. Comparison between different sequencing methods indicated that FRT is more accurate in ranking both mRNA and non-coding RNA than viral reverse transcriptase-based sequencing methods even those that specifically target these species...
April 27, 2018: RNA
Gaëlle J S Talhouarne, Joseph G Gall
We report that 7SL, the RNA component of the signal recognition particle (SRP), is an abundant ncRNA in mature red blood cells (RBCs) of human, mouse, and the frog Xenopus. 7SL RNA in RBCs is not associated with the canonical proteins of the SRP. Instead, it co-immunoprecipitates from a lysate of RBCs with a number of membrane-binding proteins. Human and mouse RBCs also contain a previously undescribed 68 nt RNA, sRN7SL, derived from the "S domain" of 7SL RNA. We discuss the possibility that 7SL RNA is selectively protected from nucleases by association with the RBC membrane...
April 23, 2018: RNA
Sarah J Fletcher, Vera P Pisareva, Abdullah Khan, Andrew Tcherepanov, Neil V Morgan, Andrey V Pisarev
Platelets are anucleate and mostly ribosome-free cells within the bloodstream, derived from megakaryocytes within bone marrow and crucial for cessation of bleeding at sites of injury. Inherited thrombocytopenias are a group of disorders characterized by a low platelet count and are frequently associated with excessive bleeding. SLFN14 is one of the most recently discovered genes linked to inherited thrombocytopenia where several heterozygous missense mutations in SLFN14 were identified to cause defective megakaryocyte maturation and platelet dysfunction...
April 20, 2018: RNA
Mosharrof Mondal, Kody Mansfield, Alex Flynt
RNAi has revolutionized genetic research, and is being commercialized as an insect pest control technology. Mechanisms exploited for this purpose are antiviral and therefore rapidly evolving. Ideally, RNAi will also be used for non-insect pests, however, differences in RNAi biology makes this uncertain. Tetranychus urticae (two-spotted spider mite) is a destructive non-insect pest, which has a proclivity to develop pesticide resistance. Here we provide a comprehensive study of the endogenous RNAi pathways of spider mites to inform design of exogenous RNAi triggers...
April 20, 2018: RNA
Adeline Pichard-Kostuch, Wenhua Zhang, Dominique Liger, Marie-Claire Daugeron, Juliette Letoquart, Ines Li de la Sierra-Gallay, Patrick Forterre, Bruno Collinet, Herman van Tilbeurgh, Tamara Basta
N6-threonyl-carbamoyl adenosine (t6A) is a universal tRNA modification found at position 37, next to the anticodon, in almost all tRNAs decoding ANN codons (where N = A, U, G or C). t6A stabilizes the codon-anticodon interaction and hence promotes translation fidelity. The first step of the biosynthesis of t6A, the production of threonyl-carbamoyl adenylate (TC-AMP), is catalyzed by the Sua5/TsaC family of enzymes. While TsaC is a single domain protein, Sua5 enzymes are composed of the TsaC-like domain, a linker and an extra domain called SUA5 of unknown function...
April 12, 2018: RNA
Samuele Negro, Marco Stazi, Marta Marchioretto, Toma Tebaldi, Umberto Rodella, Elisa Duregotti, Volker Gerke, Alessandro Quattrone, Cesare Montecucco, Michela Rigoni, Gabriella Viero
Schwann cells are key players in neuro-regeneration: they sense alarm signals released by degenerating nerve terminals and differentiate toward a pro-regenerative phenotype, with phagocytosis of nerve debris and nerve guidance. At the murine neuromuscular junction, hydrogen peroxide (H2 O2 ) is a key signal of Schwann cells activation in response to a variety of nerve injuries. Here we report that Schwann cells exposed to low doses of H2 O2 rewire the expression of several RNAs at both transcriptional and translational levels...
April 11, 2018: RNA
Stephanie L Moon, Roy Parker
Mutations in eIF2B genes cause Vanishing White Matter Disease (VWMD), a fatal leukodystrophy that can manifest following physical trauma or illness, conditions that activate the integrated stress response (ISR). EIF2B is the guanine exchange factor for eIF2, facilitating ternary complex formation and translation initiation. During the ISR, eIF2α is phosphorylated and inhibits eIF2B, causing global translation suppression and stress-induced gene translation, allowing stress adaptation and recovery. We demonstrate that VWMD patient cells hyper-suppress translation during the ISR caused by acute ER stress, delaying stress-induced gene expression and interrupting a negative feedback loop that allows translational recovery by GADD34-mediated de-phosphorylation of phospho-eIF2α...
April 9, 2018: RNA
Allen J Roth, Stewart Shuman, Beate Schwer
A seven-subunit Lsm2-8 protein ring assembles on the U-rich 3' end of the U6 snRNA. A structure-guided mutational analysis of the Saccharomyces cerevisiae Lsm2-8 ring affords new insights to structure-function relations and genetic interactions of the Lsm subunits. Alanine scanning of 39 amino acids comprising the RNA-binding sites or inter-subunit interfaces of Lsm2, Lsm3, Lsm4, Lsm5, and Lsm8 identified only one instance of lethality (Lsm3-R69A) and one severe growth defect (Lsm2-R63A), both involving amino acids that bind the 3'-terminal UUU trinucleotide...
April 3, 2018: RNA
Kijun Kim, Trung Duc Nguyen, Shaohua Li, Tuan Anh Nguyen
The Microprocessor complex, consisting of an RNase III DROSHA and the DGCR8 dimer, cleaves primary microRNA transcripts (pri-miRNAs) to initiate microRNA (miRNA) maturation. Pri-miRNAs are stem-loop RNAs, and ~79% of them contain at least one of the three major and conserved RNA motifs, UG, UGU, and CNNC. We recently demonstrated that the basal UG and apical UGU motifs of pri-miRNAs interact with DROSHA and DGCR8, respectively. They help orient Microprocessor on the pri-miRNA in a proper direction in which DROSHA and DGCR8 localize to the basal and apical pri-miRNA junctions, respectively...
April 3, 2018: RNA
Lea Shallev, Eli Kopel, Ariel Feiglin, Gil S Leichner, Dror Avni, Yehezkel Sidi, Eli Eisenberg, Aviv Barzilai, Erez Y Levanon, Shoshana Greenberger
Recognition of dsRNA molecules activates the MDA5-MAVS pathway, and plays a critical role in stimulating type-I interferon responses in psoriasis. However, the source of the dsRNA accumulation in psoriatic keratinocytes remains largely unknown. A-to-I RNA editing is a common co- or post-transcriptional modification that diversifies adenosine in dsRNA, and leads to unwinding of dsRNA structures. Thus, impaired RNA editing activity can result in an increased load of endogenous dsRNAs. Here we provide a transcriptome wide analysis of RNA editing across dozens of psoriasis patients, and demonstrate a global editing reduction in psoriatic lesions...
March 28, 2018: RNA
Sean P McClory, Kristen W Lynch, Jonathan P Ling
The fidelity of RNA splicing is regulated by a network of splicing enhancers and repressors, although the rules that govern this process are not yet fully understood. One mechanism that contributes to splicing fidelity is the repression of nonconserved cryptic exons by splicing factors that recognize dinucleotide repeats. We previously identified that TDP-43 and PTBP1/PTBP2 are capable of repressing cryptic exons utilizing UG and CU repeats, respectively. Here we demonstrate that hnRNP L (HNRNPL) also represses cryptic exons by utilizing exonic CA repeats, particularly near the 5'SS...
March 26, 2018: RNA
Kuo-Chieh Liao, Vanessa Chuo, Wy Ching Ng, Suat Peng Neo, Julien Pompon, Jayantha Gunaratne, Eng Eong Ooi, Mariano Garcia-Blanco
The four dengue viruses (DENV1-4) are rapidly re-emerging infectious RNA viruses. These positive-strand viral genomes contain structured 3' untranslated regions (UTRs) that interact with various host RNA binding proteins (RBPs). These RBPs are functionally important in viral replication, pathogenesis and defense against host immune mechanisms. Here, we combined RNA chromatography and quantitative mass spectrometry to identify proteins interacting with DENV1-4 3' UTR. As expected, RBPs displayed distinct binding specificity...
March 23, 2018: RNA
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