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RNase L

Francesca Esposito, Ilaria Carli, Claudia Del Vecchio, Lijia Xu, Angela Corona, Nicole Grandi, Dario Piano, Elias Maccioni, Simona Distinto, Cristina Parolin, Enzo Tramontano
BACKGROUND: Despite the availability of effective antiretroviral therapies, drugs for HIV-1 treatment with new mode of action are still needed. An innovative approach is aimed to identify dual HIV-1 inhibitors, small molecules that can inhibit two viral functions at the same time. Rhubarb, originated from Rheum palmatum L. and Rheum officinale Baill., is one of the earliest and most commonly used medicinal plants in Traditional Chinese Medicine (TCM) practice. We wanted to explore TCM for the identification of new chemical scaffolds with dual action abilities against HIV-1...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Madalena M Reimão-Pinto, Raphael A Manzenreither, Thomas R Burkard, Pawel Sledz, Martin Jinek, Karl Mechtler, Stefan L Ameres
The posttranscriptional addition of nucleotides to the 3' end of RNA regulates the maturation, function, and stability of RNA species in all domains of life. Here, we show that in flies, 3' terminal RNA uridylation triggers the processive, 3'-to-5' exoribonucleolytic decay via the RNase II/R enzyme CG16940, a homolog of the human Perlman syndrome exoribonuclease Dis3l2. Together with the TUTase Tailor, dmDis3l2 forms the cytoplasmic, terminal RNA uridylation-mediated processing (TRUMP) complex that functionally cooperates in the degradation of structured RNA RNA immunoprecipitation and high-throughput sequencing reveals a variety of TRUMP complex substrates, including abundant non-coding RNA, such as 5S rRNA, tRNA, snRNA, snoRNA, and the essential RNase MRP Based on genetic and biochemical evidence, we propose a key function of the TRUMP complex in the cytoplasmic quality control of RNA polymerase III transcripts...
October 11, 2016: EMBO Journal
Huning Jia, Ying Bu, Bingjie Zou, Jianping Wang, Shalen Kumar, Janet L Pitman, Guohua Zhou, Qinxin Song
Micro ribose nucleic acids (miRNAs) play an important role in biological processes such as cell differentiation, proliferation and apoptosis. Therefore, miRNAs are potentially a powerful marker for monitoring cancer and diagnosis. Here, we present sensitive signal amplification for miRNAs based on modified cycling probe technology with strand displacement amplification. miRNA was captured by the template coupled with beads, and then the first cycle based on SDA was repeatedly extended to the nicking end, which was produced by the extension reaction of miRNA...
September 30, 2016: Analyst
Enas Elkhateeb, Hassan T Tag-El-Din-Hassan, Nobuya Sasaki, Daisuke Torigoe, Masami Morimatsu, Takashi Agui
The interferon-induced oligoadenylate synthetase (OAS) family is one of the most important immune response proteins to the viral infection. The OAS protein binds dsRNA and is activated to produce 2',5'-oligoadenylates, which lead to the activation of latent form of RNase L, resulting in degradation of cellular and viral RNA and inhibition of viral replication. In mice, the Oas gene family locates on chromosome 5. The mouse Oas gene locus undergoes a recent series of duplication event, leading to the presence of eight paralogs of Oas1 genes (Oas1a through Oas1h) that forms Oas gene cluster with the Oas2, Oas3 and two OasL (OasL1 and OasL2) genes...
September 21, 2016: Infection, Genetics and Evolution
Shan Wu, Dan Tan, John L Woolford, Meng-Qiu Dong, Ning Gao
The assembly of ribosomal subunits starts in the nucleus, initiated by co-transcriptional folding of nascent ribosomal RNA (rRNA) transcripts and binding of ribosomal proteins and assembly factors. The internal transcribed spacer 2 (ITS2) is a precursor sequence to be processed from the intermediate 27S rRNA in the nucleoplasm; its removal is required for nuclear export of pre-60S particles. The proper processing of the ITS2 depends on multiple associated assembly factors and RNases. However, none of the structures of the known ITS2-binding factors is available...
September 19, 2016: Protein Science: a Publication of the Protein Society
Minh N Nguyen, Adelene Y L Sim, Yue Wan, M S Madhusudhan, Chandra Verma
RNA molecules are attractive therapeutic targets because non-coding RNA molecules have increasingly been found to play key regulatory roles in the cell. Comparing and classifying RNA 3D structures yields unique insights into RNA evolution and function. With the rapid increase in the number of atomic-resolution RNA structures, it is crucial to have effective tools to classify RNA structures and to investigate them for structural similarities at different resolutions. We previously developed the algorithm CLICK to superimpose a pair of protein 3D structures by clique matching and 3D least squares fitting...
September 14, 2016: Nucleic Acids Research
Elona Gusho, Danika Baskar, Shuvojit Banerjee
Ever since the discovery of the existence of an interferon (IFN)-regulated ribonuclease, significant advances have been made in understanding the mechanism and associated regulatory effects of its action. What had been studied initially as a "unique" endoribonuclease is currently known as ribonuclease L (RNase L where "L" stands for latent). Some of the key developments include discovery of the RNase L signaling pathway, its structural characterization, and its molecular cloning. RNase L has been implicated in antiviral and antibacterial defense, as well as in hereditary prostate cancer...
August 29, 2016: Cytokine
Clare L Kirkpatrick, Daniel Martins, Peter Redder, Antonio Frandi, Johann Mignolet, Julien Bortoli Chapalay, Marc Chambon, Gerardo Turcatti, Patrick H Viollier
Bacterial toxin-antitoxin systems (TASs) are thought to respond to various stresses, often inducing growth-arrested (persistent) sub-populations of cells whose housekeeping functions are inhibited. Many such TASs induce this effect through the translation-dependent RNA cleavage (RNase) activity of their toxins, which are held in check by their cognate antitoxins in the absence of stress. However, it is not always clear whether specific mRNA targets of orthologous RNase toxins are responsible for their phenotypic effect, which has made it difficult to accurately place the multitude of TASs within cellular and adaptive regulatory networks...
2016: Nature Microbiology
Yize Li, Susan R Weiss
: Mouse hepatitis virus strain A59 infection of mice is a useful tool for studying virus-host interaction during hepatitis development. The NS2(H126R) mutant is attenuated in liver replication due to loss of phosphodiesterase activity, which the wild-type (WT) virus uses to block the 2',5'-oligoadenylate synthetase (OAS)-RNase L (RNase L) antiviral pathway. The activation of RNase L by NS2(H126R) is cell type dependent and correlates with high basal expression levels of OAS, as found in myeloid cells...
November 1, 2016: Journal of Virology
Tad E Eichler, Brian Becknell, Robert S Easterling, Susan E Ingraham, Daniel M Cohen, Andrew L Schwaderer, David S Hains, Birong Li, Ariel Cohen, Jackie Metheny, Susheela Tridandapani, John David Spencer
Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. Because the impact of diabetes on RNase 7 expression and function are unknown, we investigated the effects of insulin on RNase 7 using human urine specimens...
September 2016: Kidney International
Ian Fish, Stéphane Boissinot
Infections with viral pathogens impose considerable selective pressure on host defensive genes. Those genes at the forefront, responsible for identifying and binding exogenous molecular viral components, will carry the hallmarks of this struggle. Oligoadenylate synthetase (OAS) enzymes play a major role in the innate defense against a large number of viruses by acting as sensors of viral infections. Following their up-regulation by the interferon pathway, OASs bind viral dsRNA and then signal ribonuclease L (RNase L) to degrade RNA, shutting down viral and host protein synthesis...
October 2016: Infection, Genetics and Evolution
Lucia Malaguarnera, Giuseppe Nunnari, Michelino Di Rosa
OBJECTIVE: The OAS proteins are characterized by their capacity to synthesize 2',5'-linked phosphodiester bonds to polymerize ATP into oligomers of adenosine. OAS3, belonging to OASs gene family, synthesizes dimeric 2-5A that binds to RNase L with low affinity and produces 2-5A oligomers shorter than the tri-tetramer 2-5As produced by other family members. METHODS: For these studies, we used the open source tools cNLS Mapper, PredictProtein and COMPARTMENTS for the nuclear localization signal prediction, UCSF Chimera for molecular graphics and analyses, The Human Protein Atlas to confirm with the IF the OAS3 cell localization and Ensembl Variation Table to identify the presence of putative single nucleotide polymorphisms in the NLS sequence identification...
July 5, 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Yoshiaki Kitamura, Seiya Kito, Remi Nakashima, Katsuki Tanaka, Kumi Nagaoka, Yukio Kitade
RNase L is activated by 2',5'-oligoadenylates (2-5A) at subnanomolar levels to cleave single-stranded RNA. We previously reported the hypothesis that the introduction of an 8-methyladenosine residue at the 2'-terminus of the 2-5A tetramer shifts the 2-5A binding site of RNase L. In this study, we synthesized various 5'-modified 2-5A analogs with 8-methyladenosine at the 2'-terminus. The doxifluridine-conjugated 8-methyladenosine-substituted 2-5A analog was significantly more effective as an activator of RNase L than the parent 5'-monophophorylated 2-5A tetramer and showed a tumor suppressive effect against human cervical cancer cells...
August 15, 2016: Bioorganic & Medicinal Chemistry
Samuel Mang, Hannes Bucher, Peter Nickolaus
The scintillation proximity assay (SPA) technology has been widely used to establish high throughput screens (HTS) for a range of targets in the pharmaceutical industry. PDE12 (aka. 2´-phosphodiesterase) has been published to participate in the degradation of oligoadenylates that are involved in the establishment of an antiviral state via the activation of ribonuclease L (RNAse-L). Degradation of oligoadenylates by PDE12 terminates these antiviral activities, leading to decreased resistance of cells for a variety of viral pathogens...
June 22, 2016: Current Drug Discovery Technologies
Ruikang Liu, Bernard Moss
UNLABELLED: Vaccinia virus (VACV) decapping enzymes and cellular exoribonuclease Xrn1 catalyze successive steps in mRNA degradation and prevent double-stranded RNA (dsRNA) accumulation, whereas the viral E3 protein can bind dsRNA. We showed that dsRNA and E3 colocalized within cytoplasmic viral factories in cells infected with a decapping enzyme mutant as well as with wild-type VACV and that they coprecipitated with antibody. An E3 deletion mutant induced protein kinase R (PKR) and eukaryotic translation initiation factor alpha (eIF2α) phosphorylation earlier and more strongly than a decapping enzyme mutant even though less dsRNA was made, leading to more profound effects on viral gene expression...
September 1, 2016: Journal of Virology
Kensuke Miyake, Takuma Shibata, Umeharu Ohto, Toshiyuki Shimizu
Nucleic acid (NA) is continuously degraded in lysosomes, cytoplasm, and nucleus. NA degradation has a key role in preventing hazardous activation of NA sensors. DNA degradation by lysosomal and cytoplasmic DNases prevents homeostatic activation of cytoplasmic DNA sensing pathways. Crude NA, however, is not sufficient for stimulating NA sensors. mRNAs and rRNAs need to be processed by inositol-requiring enzyme 1 (IRE-1) or RNase L before stimulating cytoplasmic RNA sensors. Activation of cytoplasmic RNA sensors by processed RNAs is tightly controlled by their degradation through the machineries, such as RNA editing, by adenosine (A) deaminases that act on RNA 1 (ADAR1) and the RNA exosome...
June 22, 2016: Journal of Leukocyte Biology
Xuhua Tang, Yiping Zhu, Stacey L Baker, Matthew W Bowler, Benjamin Jieming Chen, Chen Chen, J Robert Hogg, Stephen P Goff, Haiwei Song
Retroviral reverse transcriptase (RT) of Moloney murine leukemia virus (MoMLV) is expressed in the form of a large Gag-Pol precursor protein by suppression of translational termination in which the maximal efficiency of stop codon read-through depends on the interaction between MoMLV RT and peptidyl release factor 1 (eRF1). Here, we report the crystal structure of MoMLV RT in complex with eRF1. The MoMLV RT interacts with the C-terminal domain of eRF1 via its RNase H domain to sterically occlude the binding of peptidyl release factor 3 (eRF3) to eRF1...
2016: Nature Communications
Ye Tian, Xin Tian, Xu Han, Yong Chen, Cheng-Yang Song, Yan-Bin Zhang, Da-Li Tian
ATP binding cassette E1 (ABCE1), a member of the family of ATP binding cassette transporters, has initially emerged as an RNase L inhibitor. As a highly conserved protein, it is involved in capsid assembly and translation processes of the human immunodeficiency virus as well as in tumor development and progression. Studies have shown that ABCE1 protein was overexpressed in lung carcinoma tissues and metastatic lymph nodes compared to normal lung tissues. However, little is known about the roles of ABCE1 in lung cancer...
August 2016: Molecular Medicine Reports
Nicole S Spoelstra, Diana M Cittelly, Jessica L Christenson, Michael A Gordon, Anthony Elias, Paul Jedlicka, Jennifer K Richer
Dicer is an RNase III enzyme responsible for cleaving double-stranded RNAs into small interfering RNAs and microRNAs, which either target messenger RNA transcripts for degradation or inhibit translation. Dicer protein levels have been examined in breast cancer with contradictory results. Our goal was to resolve whether Dicer levels differ in breast cancer versus normal breast epithelium and between estrogen receptor-α-positive (ER+) or estrogen receptor-α-negative (ER-) primary breast cancers. We compared 3 different Dicer antibodies: Abcam 4A6, Abcam ab5818, and Sigma HPA000694, using immunohistochemistry and Western blot analyses...
October 2016: Human Pathology
Michael H Hayes, Daniel L Weeks
A hallmark of Alzheimer's, Huntington's and similar diseases is the assembly of proteins into amyloids rather than folding into their native state. There is an increasing appreciation that amyloids, under specific conditions, may be non-pathogenic. Here we show that amyloids form as a normal part of Xenopus oocyte development. Amyloids are detectable in the cytosol and the nucleus using an amyloid binding dye and antibodies that recognize amyloid structure. In the cytosol, yolk platelets are amyloid reactive, as are a number of yet to be characterized particles...
2016: Biology Open
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