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Rnase h

Rintaro Iwata Hara, Yuki Hisada, Yusuke Maeda, Takanori Yokota, Takeshi Wada
Heteroduplex oligonucleotides (HDOs), composed of a DNA/LNA gapmer and its complementary RNA, are a novel, promising candidates for antisense drugs. We previously reported oligodiaminogalactoses (ODAGals), designed to bind to A-type nucleic acid duplexes such as DNA/RNA and RNA/RNA duplexes. In this paper, we report oligodiguanidinogalactoses (ODGGals) as novel A-type duplex binding molecules. We aimed to study in detail applicability of ODAGals and ODGGals for additives to HDOs as an antisense drug. The effect of ODAGal4 (ODAGal 4mer) and ODGGal3 (ODGGal 3mer) on an HDO were evaluated by UV melting analyses, RNA degradation study by ribonuclease A (RNase A), and ribonuclease H (RNase H)...
March 12, 2018: Scientific Reports
Purushottam R Lomate, Bryony C Bonning
Management of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), an invasive, agricultural pest in the United States, has presented significant challenges. This polyphagous insect uses both extra-oral and gut-based digestion thwarting protein- or nucleotide-based control strategies. The objective of this study was to biochemically characterize the digestive enzymes (proteases and nucleases) from the saliva, salivary gland and the gut of H. halys. Enzyme profiles for the two tissues and saliva radically differ: The pH optimum for proteases in the gut was six, with cysteine proteases predominant...
March 12, 2018: Archives of Insect Biochemistry and Physiology
Kefeng Wu, Changbei Ma, Zhiyi Deng, Ning Fang, Zhenwei Tang, Xingxing Zhu, Kemin Wang
In this paper, we describe a novel, label-free and nicking enzyme-assisted fluorescence signal amplification strategy that demonstrates to be cost efficient, sensitive, and unique for assaying the RNase H activity and inhibition based on G-quadruplex formation using a thioflavin T (ThT) dye. This novel assay method is able to detect RNase H with a detection limit of 0.03 U /mL and further exhibits a good linearity R2 = 0.9923 at a concentration range of 0.03-1 U/mL under optimized conditions. Moreover, the inhibition effect of gentamycin on the RNase H activity is also studied...
May 15, 2018: Talanta
Andreas Dieckmann, Peter H Hagedorn, Yvonne Burki, Christine Brügmann, Marco Berrera, Martin Ebeling, Thomas Singer, Franz Schuler
The successful development of high-affinity gapmer antisense oligonucleotide (ASO) therapeutics containing locked nucleic acid (LNA) or constrained ethyl (cEt) substitutions has been hampered by the risk of hepatotoxicity. Here, we present an in vitro approach using transfected mouse fibroblasts to predict the potential hepatic liabilities of LNA-modified ASOs (LNA-ASOs), validated by assessing 236 different LNA-ASOs with known hepatotoxic potential. This in vitro assay accurately reflects in vivo findings and relates hepatotoxicity to RNase H1 activity, off-target RNA downregulation, and LNA-ASO-binding affinity...
March 2, 2018: Molecular Therapy. Nucleic Acids
Stefano Misino, Diego Bonetti, Sarah Luke-Glaser, Brian Luke
Cancer cells activate telomere maintenance mechanisms (TMMs) to bypass replicative senescence and achieve immortality by either upregulating telomerase or promoting homology-directed repair (HDR) at chromosome ends to maintain telomere length, the latter being referred to as ALT (Alternative Lengthening of Telomeres). In yeast telomerase mutants, the HDR-based repair of telomeres leads to the generation of 'survivors' that escape senescence and divide indefinitely. So far, yeast has proven to provide an accurate model to study the generation and maintenance of telomeres via HDR...
February 16, 2018: Differentiation; Research in Biological Diversity
Nalini Raghunathan, Rajvardhan M Kapshikar, Jakku K Leela, Jillella Mallikarjun, Philippe Bouloc, Jayaraman Gowrishankar
Transcription termination by Rho is essential for viability in various bacteria, including some major pathogens. Since Rho acts by targeting nascent RNAs that are not simultaneously translated, it also regulates antisense transcription. Here we show that RNase H-deficient mutants of Escherichia coli exhibit heightened sensitivity to the Rho inhibitor bicyclomycin, and that Rho deficiency provokes increased formation of RNA-DNA hybrids (R-loops) which is ameliorated by expression of the phage T4-derived R-loop helicase UvsW...
February 21, 2018: Nucleic Acids Research
Stanley M H Chan, Mark P Lowe, Ashton Bernard, Alyson A Miller, Terence P Herbert
Inositol Requiring Enzyme 1 alpha (IRE1α) is an ER-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common disease including diabetes, cancer and neurological pathologies such as Huntington's and Alzheimer's disease. 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity in mechanistic studies (IC50 of 6...
February 20, 2018: Biochemical Journal
Danyun Zeng, Benjamin P Brown, Markus W Voehler, Sheng Cai, Nicholas J Reiter
Ribonuclase P (RNase P) is an essential metallo-endonuclease that catalyzes 5' precursor-tRNA (ptRNA) processing and exists as an RNA-based enzyme in bacteria, archaea, and eukaryotes. In bacteria, a large catalytic RNA and a small protein component assemble to recognize and accurately cleave ptRNA and tRNA-like molecular scaffolds. Substrate recognition of ptRNA by bacterial RNase P requires RNA-RNA shape complementarity, intermolecular base pairing, and a dynamic protein-ptRNA binding interface. To gain insight into the binding specificity and dynamics of the bacterial protein-ptRNA interface, we report the backbone and side chain 1 H, 13 C, and 15 N resonance assignments of the hyperthermophilic Thermatoga maritima RNase P protein in solution at 318 K...
February 15, 2018: Biomolecular NMR Assignments
Gregoire Masliah, Christophe Maris, Sebastian Lb König, Maxim Yulikov, Florian Aeschimann, Anna L Malinowska, Julie Mabille, Jan Weiler, Andrea Holla, Juerg Hunziker, Nicole Meisner-Kober, Benjamin Schuler, Gunnar Jeschke, Frederic H-T Allain
The accurate cleavage of pre-micro(mi)RNAs by Dicer and mi/siRNA guide strand selection are important steps in forming the RNA-induced silencing complex (RISC). The role of Dicer binding partner TRBP in these processes remains poorly understood. Here, we solved the solution structure of the two N-terminal dsRNA binding domains (dsRBDs) of TRBP in complex with a functionally asymmetric siRNA using NMR, EPR, and single-molecule spectroscopy. We find that siRNA recognition by the dsRBDs is not sequence-specific but rather depends on the RNA shape...
February 15, 2018: EMBO Journal
Alexander J Neil, Miranda U Liang, Alexandra N Khristich, Kartik A Shah, Sergei M Mirkin
Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA-DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich's ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA-DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed...
February 13, 2018: Nucleic Acids Research
Yan Wang, Jing Tang, Zhengqiang Wang, Robert J Geraghty
Human cytomegalovirus terminase complex cleaves the concatemeric genomic viral DNA into unit lengths during genome packaging and particle assembly. Terminase complex ATPase and endonuclease activity is provided by the viral protein pUL89. pUL89 is an attractive drug target because its activities are required for infectious virus production. A domain located in the C-terminus of pUL89 has an RNase H/integrase-like fold and endonuclease activity that can be inhibited by compounds featuring a chelating triad motif...
February 6, 2018: Antiviral Research
Cinzia Sanna, Daniela Rigano, Angela Corona, Dario Piano, Carmen Formisano, Domenica Farci, Genni Franzini, Mauro Ballero, Giuseppina Chianese, Enzo Tramontano, Orazio Taglialatela-Scafati, Francesca Esposito
During our search for potential templates of HIV-1 reverse transcriptase (RT) and integrase (IN) dual inhibitors, the methanolic extract obtained from aerial parts of Limonium morisianum was investigated. Repeated bioassay-guided chromatographic purifications led to the isolation of the following secondary metabolites: myricetin, myricetin 3-O-rutinoside, myricetin-3-O-(6″-O-galloyl)-β-d-galactopyranoside, (-)-epigallocatechin 3-O-gallate, tryptamine, ferulic and phloretic acids. The isolated compounds were tested on both HIV-1 RT-associated RNase H and IN activities...
February 4, 2018: Natural Product Research
Liang Chen, Jia-Yu Chen, Yi-Jou Huang, Ying Gu, Jinsong Qiu, Hao Qian, Changwei Shao, Xuan Zhang, Jing Hu, Hairi Li, Shunmin He, Yu Zhou, Omar Abdel-Wahab, Dong-Er Zhang, Xiang-Dong Fu
Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway...
February 1, 2018: Molecular Cell
Di Chen, Brandon J Dixon, Desislava M Doycheva, Bo Li, Yang Zhang, Qin Hu, Yue He, Zongduo Guo, Derek Nowrangi, Jerry Flores, Valery Filippov, John H Zhang, Jiping Tang
BACKGROUND: The endoplasmic reticulum (ER) is responsible for the control of correct protein folding and protein function which is crucial for cell survival. However, under pathological conditions, such as hypoxia-ischemia (HI), there is an accumulation of unfolded proteins thereby triggering the unfolded protein response (UPR) and causing ER stress which is associated with activation of several stress sensor signaling pathways, one of them being the inositol requiring enzyme-1 alpha (IRE1α) signaling pathway...
February 2, 2018: Journal of Neuroinflammation
Hong Xie, Chih-Hang Anthony Tang, Jun H Song, Anthony Mancuso, Juan R Del Valle, Jin Cao, Yan Xiang, Chi V Dang, Roy Lan, Danielle J Sanchez, Brian Keith, Chih-Chi Andrew Hu, M Celeste Simon
Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the IRE1α-XBP1 pathway through multiple molecular mechanisms in a variety of c-Myc- and N-Myc-dependent cancers. In particular, Myc-overexpressing cells require IRE1α-XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity...
January 30, 2018: Journal of Clinical Investigation
Mahesh Khatri, Levi Arthur Richardson, Tea Meulia
BACKGROUND: Mesenchymal stem (stromal) cells (MSCs) mediate their immunoregulatory and tissue repair functions by secreting paracrine factors, including extracellular vesicles (EVs). In several animal models of human diseases, MSC-EVs mimic the beneficial effects of MSCs. Influenza viruses cause annual outbreaks of acute respiratory illness resulting in significant mortality and morbidity. Influenza viruses constantly evolve, thus generating drug-resistant strains and rendering current vaccines less effective against the newly generated strains...
January 29, 2018: Stem Cell Research & Therapy
Lanfang Wang, Mahrou Sadri, David Giraud, Janos Zempleni
Background: Evidence suggests that dietary microRNAs (miRs) are bioavailable and regulate gene expression across species boundaries. Concerns were raised that the detection of dietary miRs in plasma might have been due to sample contamination or lack of assay specificity. Objectives: The objectives of this study were to assess potential confounders of plasma miR analysis and to detect miRs from bovine milk in human plasma. Methods: Potential confounders of plasma miR analysis (circadian rhythm, sample collection and storage, calibration, and erythrocyte hemolysis) were assessed by quantitative reverse transcriptase polymerase chain reaction (PCR) by using blood from healthy adults (7 men, 6 women; aged 23-57 y)...
January 1, 2018: Journal of Nutrition
Flor Torres-Juarez, Lousseine Touqui, Juan Leon-Contreras, Cesar Rivas-Santiago, Jose A Enciso-Moreno, Rogelio Hernández-Pando, Bruno Rivas-Santiago
Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb). Innate immunity is the first line of defense against Mtb and malfunctions in any of its components is associated with the susceptibility to the disease. Epithelial products, such as host defence peptides (HDP) are the first molecules produced to counteract the infection. Although a wide variety of HDP are produced by epithelial cells only few of them have been studied during Mtb infection. Here, we assessed the expression and production of the HDPs: psoriasin, sPLA2-IIA and RNase 7 in airway epithelial cells (NCI-H292), type II pneumocytes (A549 cells) and monocytes-derived macrophages from human peripheral blood mononuclear cells (bMDM) and from the human cell line THP1(MDM) after Mtb in vitro infection...
January 16, 2018: Pathogens and Disease
Chandra H McAllister, Colleen E Fortier, Kate R St Onge, Bianca M Sacchi, Meaghan J Nawrot, Troy Locke, Janice E K Cooke
Mountain pine beetle (Dendroctonus ponderosae Hopkins; MPB) is an economically and ecologically important pest of pine species in western North America. Mountain pine beetles form complex multipartite relationships with microbial partners, including the ophiostomoid fungi Grosmannia clavigera (Robinson-Jeffrey and Davidson) Zipfel, de Beer and Wingfield, Ophiostoma montium (Rumbold) von Arx, Grosmannia aurea (Robinson-Jeffrey and Davidson) Zipfel, de Beer and Wingfield, Leptographium longiclavatum (Lee, Kim, and Breuil) and Leptographium terebrantis (Barras and Perry)...
January 10, 2018: Tree Physiology
Thomas B Hansen
Circular RNAs (circRNAs) constitute a novel subset in the fascinating world of noncoding RNA, and they are found in practically all eukaryotes. Most of them exhibit low expression levels but some are extremely abundant. Typically, circRNAs are studied by RT-PCR-based assays, but for certain types of analyses this technique is not suitable. Circular RNA with repetitive exons (circular concatemers) has been observed by us and others when transiently expressing circRNAs in cells, however techniques and assays to study these species have not been established...
2018: Methods in Molecular Biology
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