Biochemical Mechanisms of the RNA-Induced Silencing Complex
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Not Dicer but Argonaute Is Required for a Microrna Production
Cell Research (2010) 20:735-737. npg © 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr A new twist in the microRNA pathway: Not Dicer but Argonaute is required for a microRNA production Gabriel D Bossé1, Martin J Simard1 1Laval University Cancer Research Centre, Hôtel-Dieu de Québec (CHUQ), Quebec City, Québec G1R 2J6, Canada Cell Research (2010) 20:735-737. doi:10.1038/cr.2010.83; published online 15 June 2010 Found in all metazoans, microRNAs A Canonical pathway B Ago2-dependent pathway or miRNAs are small non-coding RNA Nucleus Cytoplasm Nucleus Cytoplasm of ~22 nucleotides in length that com- Exp.5 Exp.5 pletely reshaped our understanding of gene regulation. This new class of gene pre-miR-451 regulator is mostly transcribed by the pre-miRNA RNA polymerase II producing a long stem-loop structure, called primary- or Ago2 pri-miRNA, that will first be processed Ago2 Dicer in the cell nucleus by a multiprotein TRBP complex called microprocessor to gen- erate a shorter RNA structure called Ago2 RISC precursor- or pre-miRNA. The precisely Ago2 RISC processed pre-miRNA will next be ex- ported into the cytoplasm by Exportin 5 and loaded onto another processing machine containing the ribonuclease III enzyme Dicer, an Argonaute protein Ago2 Ago2 and other accessory cellular factors mRNA mRNA (Figure 1A; [1]). Dicer will mediate the Translation inhibition Translation inhibition cleavage of the pre-miRNA to form the mature miRNA that will then be bound Figure 1 (A) Canonical microRNA biogenesis. In mammals, the pre-miRNA is by the Argonaute protein to form, most loaded onto a multiprotein complex consisting minimally of Dicer, Tar RNA Bind- likely with other cellular factors, the ef- ing Protein (TRBP) and Ago2. -
RNA Interference in the Nucleus: Roles for Small Rnas in Transcription, Epigenetics and Beyond
REVIEWS NON-CODING RNA RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond Stephane E. Castel1 and Robert A. Martienssen1,2 Abstract | A growing number of functions are emerging for RNA interference (RNAi) in the nucleus, in addition to well-characterized roles in post-transcriptional gene silencing in the cytoplasm. Epigenetic modifications directed by small RNAs have been shown to cause transcriptional repression in plants, fungi and animals. Additionally, increasing evidence indicates that RNAi regulates transcription through interaction with transcriptional machinery. Nuclear small RNAs include small interfering RNAs (siRNAs) and PIWI-interacting RNAs (piRNAs) and are implicated in nuclear processes such as transposon regulation, heterochromatin formation, developmental gene regulation and genome stability. RNA interference Since the discovery that double-stranded RNAs (dsRNAs) have revealed a conserved nuclear role for RNAi in (RNAi). Silencing at both the can robustly silence genes in Caenorhabditis elegans and transcriptional gene silencing (TGS). Because it occurs post-transcriptional and plants, RNA interference (RNAi) has become a new para- in the germ line, TGS can lead to transgenerational transcriptional levels that is digm for understanding gene regulation. The mecha- inheritance in the absence of the initiating RNA, but directed by small RNA molecules. nism is well-conserved across model organisms and it is dependent on endogenously produced small RNA. uses short antisense RNA to inhibit translation or to Such epigenetic inheritance is familiar in plants but has Post-transcriptional gene degrade cytoplasmic mRNA by post-transcriptional gene only recently been described in metazoans. silencing silencing (PTGS). PTGS protects against viral infection, In this Review, we cover the broad range of nuclear (PTGS). -
RNA Stem Structure Governs Coupling of Dicing and Gene Silencing in RNA
RNA stem structure governs coupling of dicing and PNAS PLUS gene silencing in RNA interference Hye Ran Koha,b,1, Amirhossein Ghanbariniakia,c,d, and Sua Myonga,c,d,1 aDepartment of Biophysics, Johns Hopkins University, Baltimore, MD 21218; bDepartment of Chemistry, Chung-Ang University, Seoul 06974, Korea; cInstitute for Genomic Biology, University of Illinois, Urbana, IL 61801; and dCenter for Physics of Living Cells, University of Illinois, Urbana, IL 61801 Edited by Brenda L. Bass, University of Utah School of Medicine, Salt Lake City, UT, and approved October 13, 2017 (received for review June 8, 2017) PremicroRNAs (premiRNAs) possess secondary structures consist- coworkers (20), but its relationship to the silencing efficiency has ing of a loop and a stem with multiple mismatches. Despite the not been tested. While the effect of mismatches between the well-characterized RNAi pathway, how the structural features of guide strand and target mRNA has been extensively studied (21– premiRNA contribute to dicing and subsequent gene-silencing 24), the effect of mismatch between guide and passenger strand efficiency remains unclear. Using single-molecule FISH, we dem- has not been systematically examined. onstrate that cytoplasmic mRNA, but not nuclear mRNA, is reduced We sought to study how different structural features found in during RNAi. The dicing rate and silencing efficiency both increase premiRNAs and presiRNAs modulate overall gene-silencing in a correlated manner as a function of the loop length. In contrast, efficiency by measuring two key steps in the RNAi pathway: (i) mismatches in the stem drastically diminish the silencing efficiency dicing kinetics to measure how quickly premiRNA or presiRNA without impacting the dicing rate. -
INTRODUCTION Sirna and Rnai
J Korean Med Sci 2003; 18: 309-18 Copyright The Korean Academy ISSN 1011-8934 of Medical Sciences RNA interference (RNAi) is the sequence-specific gene silencing induced by dou- ble-stranded RNA (dsRNA). Being a highly specific and efficient knockdown tech- nique, RNAi not only provides a powerful tool for functional genomics but also holds Institute of Molecular Biology and Genetics and School of Biological Science, Seoul National a promise for gene therapy. The key player in RNAi is small RNA (~22-nt) termed University, Seoul, Korea siRNA. Small RNAs are involved not only in RNAi but also in basic cellular pro- cesses, such as developmental control and heterochromatin formation. The inter- Received : 19 May 2003 esting biology as well as the remarkable technical value has been drawing wide- Accepted : 23 May 2003 spread attention to this exciting new field. V. Narry Kim, D.Phil. Institute of Molecular Biology and Genetics and School of Biological Science, Seoul National University, San 56-1, Shillim-dong, Gwanak-gu, Seoul 151-742, Korea Key Words : RNA Interference (RNAi); RNA, Small interfering (siRNA); MicroRNAs (miRNA); Small Tel : +82.2-887-8734, Fax : +82.2-875-0907 hairpin RNA (shRNA); mRNA degradation; Translation; Functional genomics; Gene therapy E-mail : [email protected] INTRODUCTION established yet, testing 3-4 candidates are usually sufficient to find effective molecules. Technical expertise accumulated The RNA interference (RNAi) pathway was originally re- in the field of antisense oligonucleotide and ribozyme is now cognized in Caenorhabditis elegans as a response to double- being quickly applied to RNAi, rapidly improving RNAi stranded RNA (dsRNA) leading to sequence-specific gene techniques. -
Annale D890ahlfors.Pdf (5.211Mb)
TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS SARJA - SER. D OSA - TOM. 890 MEDICA - ODONTOLOGICA INTERLEUKIN-4 INDUCED LEUKOCYTE DIFFERENTIATION by Helena Ahlfors TURUN YLIOPISTO UNIVERSITY OF TURKU Turku 2009 From Turku Centre for Biotechnology, University of Turku and Åbo Akademi University; Department of Medical Biochemistry and Molecular Biology, University of Turku and National Graduate School of Informational and Structural Biology Supervised by Professor Riitta Lahesmaa, M.D., Ph.D. Turku Centre for Biotechnology University of Turku and Åbo Akademi University Turku, Finland Reviewed by Professor Risto Renkonen M.D., Ph.D. Transplantation laboratory Haartman Institute University of Helsinki Helsinki, Finland and Docent Panu Kovanen, M.D., Ph.D. Haartman Institute Department of Pathology University of Helsinki Helsinki, Finland Opponent Assistant Professor Mohamed Oukka, Ph.D. Seattle Children’s Research Institute Department of Immunology University of Washington Seattle, USA ISBN 978-951-29-4183-4 (PRINT) ISBN 978-951-29-4184-1 (PDF) ISSN 0355-9483 Painosalama Oy – Turku, Finland 2009 Think where mans glory most begins and ends, and say my glory was I had such friends. William Butler Yeats (1865 – 1939) ABSTRACT Helena Ahlfors Interleukin-4 induced leukocyte differentiation Turku Centre for Biotechnology, University of Turku and Åbo Akademi University Department of Medical Biochemistry and Genetics, University of Turku National Graduate School of Informational and Structural Biology, 2009 Monocytes, macrophages and dendritic cells (DCs) are important mediators of innate immune system, whereas T lymphocytes are the effector cells of adaptive immune responses. DCs play a crucial role in bridging innate and adaptive immunity. Naïve CD4+ Th progenitors (Thp) differentiate to functionally distinct effector T cell subsets including Th1, Th2 and Th17 cells, which while being responsible for specific immune functions have also been implicated in pathological responses, such as autoimmunity, asthma and allergy. -
Gene Silencing: Double-Stranded RNA Mediated Mrna Degradation and Gene Inactivation
Cell Research (2001); 11(3):181-186 http://www.cell-research.com REVIEW Gene silencing: Double-stranded RNA mediated mRNA degradation and gene inactivation 1, 2 1 TANG WEI *, XIAO YAN LUO , VANESSA SANMUELS 1 North Carolina State University, Forest Biotechnology Group, Raleigh, NC 27695, USA 2 University of North Carolina, Department of Cell and Developmental Biology, Chapel Hill, NC 27599, USA ABSTRACT The recent development of gene transfer approaches in plants and animals has revealed that transgene can undergo silencing after integration in the genome. Host genes can also be silenced as a consequence of the presence of a homologous transgene. More and more investigations have demonstrated that double- stranded RNA can silence genes by triggering degradation of homologous RNA in the cytoplasm and by directing methylation of homologous nuclear DNA sequences. Analyses of Arabidopsis mutants and plant viral suppressors of silencing are unraveling RNA-silencing mechanisms and are assessing the role of me- thylation in transcriptional and posttranscriptional gene silencing. This review will focus on double-stranded RNA mediated mRNA degradation and gene inactivation in plants. Key words: Gene silencing, double-stranded RNA, methylation, homologous RNA, transgene. INTRODUCTION portant in consideration of its practical application The genome structure of plants can be altered by over the the past ten years[1-5]. Transgenes can genetic transformation. During the process of gene become silent after a long phase of expression, and transfer, Agrobacterium tumefaciens integrate part can sometimes silence the expression of homologous of their genome into the genome of susceptible elements located at ectopic positions in the genome. -
Beyond Microrna Â
Cancer Letters xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Mini-review Beyond microRNA – Novel RNAs derived from small non-coding RNA and their implication in cancer ⇑ Elena S. Martens-Uzunova , Michael Olvedy, Guido Jenster Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands article info abstract Article history: Over the recent years, Next Generation Sequencing (NGS) technologies targeting the microRNA transcrip- Available online xxxx tome revealed the existence of many different RNA fragments derived from small RNA species other than microRNA. Although initially discarded as RNA turnover artifacts, accumulating evidence suggests that Keywords: RNA fragments derived from small nucleolar RNA (snoRNA) and transfer RNA (tRNA) are not just random snoRNA-derived RNA (sdRNA) degradation products but rather stable entities, which may have functional activity in the normal and tRNA fragment (tRF) malignant cell. Next generation sequencing This review summarizes new findings describing the detection and alterations in expression of Cancer snoRNA-derived (sdRNA) and tRNA-derived (tRF) RNAs. We focus on the possible interactions of sdRNAs microRNA Non-coding RNA and tRFs with the canonical microRNA pathways in the cell and present current hypotheses on the func- tion of these RNAs. Ó 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Alongside with miRNA, other types of small regulatory ncRNAs like exogenous and endogenous small interfering RNAs (siRNAs Within less than a decade since the sequencing of the human and endo-siRNAs) [6–8] and PiWi-interacting RNAs (piRNAs) [9] genome it became clear that over ninety percent of our genes en- are also involved in gene regulation and genome defense and share code for RNA transcripts that never get translated to protein. -
RNA Interference: Silencing in the Cytoplasm and Nucleus Nathaniel R Dudley & Bob Goldstein*
113 RNA interference: Silencing in the cytoplasm and nucleus Nathaniel R Dudley & Bob Goldstein* Address quelling in fungi [7]. RNAi has since become widely used to Biology Department suppress the function of specific genes. In the age of genomics, University of North Carolina RNAi has proved a valuable tool that enables researchers to 616 Fordham Hall Chapel Hill study a number of important processes such as cell death, NC 27599-3280 development and cancer [1]. USA Email: [email protected] RNAi in the cytoplasm *To whom correspondence should be addressed Recent genetic and biochemical research in several systems has greatly improved our understanding of how RNAi works Current Opinion in Molecular Therapeutics 2003 5(2):113-117 (Figure 1). A dsRNA-binding protein recognizes introduced Current Drugs ISSN 1464-8431 dsRNAs that are typically several hundred nucleotide pairs long [8]. This dsRNA-binding protein associates with Dicer, an Although the discovery that double-stranded RNA is able to silence RNaseIII-related enzyme, that dices the introduced dsRNA into gene expression was only made five years ago, methods for small duplexes (21 to 25 nucleotides long) [8,9••,10••,11•]. These experimentally silencing genes have already been extended into a small duplexes, called small interfering RNAs (siRNAs), then act broad diversity of organisms, including human cells. RNA as guides in association with a large protein complex to target interference has also been discovered to function in physiological transcripts for degradation. The siRNA/protein complex is gene silencing. RNA interference works by causing degradation of termed an RNA-induced silencing complex (RISC) [12,13••,14••] targeted mRNAs in the cytoplasm. -
Interference Interfering RNA-Mediated RNA Inhibition Of
Inhibition of HIV-1 Infection by Small Interfering RNA-Mediated RNA Interference John Capodici, Katalin Karikó and Drew Weissman This information is current as J Immunol 2002; 169:5196-5201; ; of September 29, 2021. doi: 10.4049/jimmunol.169.9.5196 http://www.jimmunol.org/content/169/9/5196 Downloaded from References This article cites 27 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/169/9/5196.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Inhibition of HIV-1 Infection by Small Interfering RNA-Mediated RNA Interference1 John Capodici,* Katalin Kariko´,† and Drew Weissman2* RNA interference (RNAi) is an ancient antiviral response that processes dsRNA and associates it into a nuclease complex that identifies RNA with sequence homology and specifically cleaves it. -
The Argonaute Family: Tentacles That Reach Into Rnai, Developmental Control, Stem Cell Maintenance, and Tumorigenesis
Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis Michelle A. Carmell,1,2,3 Zhenyu Xuan,1,3 Michael Q. Zhang,1 and Gregory J. Hannon1,4 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 2Program in Genetics, State University of New York at Stony Brook, Stony Brook, New York 11794, USA RNA interference (RNAi) is an evolutionarily conserved The Argonaute family process through which double-stranded RNA (dsRNA) Argonaute proteins make up a highly conserved family induces the silencing of cognate genes (for review, see whose members have been implicated in RNAi and re- Bernstein et al. 2001b; Carthew 2001). Sources of dsRNA lated phenomena in several organisms. In addition to silencing triggers include experimentally introduced roles in RNAi-like mechanisms, Argonaute proteins in- dsRNAs, RNA viruses, transposons, and RNAs tran- fluence development, and at least a subset are involved scribed from complex transgene arrays (for review, see in stem cell fate determination. Argonaute proteins are Hammond et al. 2001b). Short hairpin sequences en- ∼100-kD highly basic proteins that contain two common coded in the genome also appear to enter the RNAi path- domains, namely PAZ and PIWI domains (Cerutti et al. way and function to regulate the expression of endog- 2000). The PAZ domain, consisting of 130 amino acids, enous, protein-coding genes (Grishok et al. 2001; has been identified in Argonaute proteins and in Dicer Hutvagner et al. 2001; Ketting et al. -
Dan Graur Department of Biology & Biochemistry University Of
Down with ncRNA! Long live fRNA and jRNA! Dan Graur Department of Biology & Biochemistry University of Houston Science & Research Building 2 3455 Cullen Blvd. Suite #342 Houston, TX 77204-5001 Voice: 713-743-7236 Fax: 713-743-2636 Email: [email protected] 1 Abstract Noncoding RNA (ncRNA) and long noncoding RNA (lncRNA) are scientifically invalid terms because they define molecular entities according to properties they do not possess and functions they do not perform. Here, I suggest retiring these two terms. Instead, I suggest using an evolutionary classification of genomic function, in which every RNA molecule is classified as either “functional” or “junk” according to its selected effect function. Dealing with RNA molecules whose functional status is unknown require us to phrase Popperian nomenclatures that spell out the conditions for their own refutation. Thus, in the absence of falsifying evidence, RNA molecules of unknown function must be considered junk RNA (jRNA). 2 Negative descriptions in biology are generally considered invalid. That is, biological entities cannot be solely defined by what they do not possess or do not do. Hence, for instance, the taxon Pisces (fishes) has been deemed scientifically invalid even before its monophyletic status was refuted, because the definition of Pisces involved a single negative character state—the lack of limbs with digits. The same principles should apply to the taxonomy of molecular entities. In the scientific literature, the modifiers “non-coding,” “noncoding,” and “nc” are widely used as prefixes for “DNA” and “RNA.” As of September 1, 2017, these terms appear more than 45,000 times in Google Scholar. -
RNA Silencing-Based Improvement of Antiviral Plant Immunity
viruses Review Catch Me If You Can! RNA Silencing-Based Improvement of Antiviral Plant Immunity Fatima Yousif Gaffar and Aline Koch * Centre for BioSystems, Institute of Phytopathology, Land Use and Nutrition, Justus Liebig University, Heinrich-Buff-Ring 26, D-35392 Giessen, Germany * Correspondence: [email protected] Received: 4 April 2019; Accepted: 17 July 2019; Published: 23 July 2019 Abstract: Viruses are obligate parasites which cause a range of severe plant diseases that affect farm productivity around the world, resulting in immense annual losses of yield. Therefore, control of viral pathogens continues to be an agronomic and scientific challenge requiring innovative and ground-breaking strategies to meet the demands of a growing world population. Over the last decade, RNA silencing has been employed to develop plants with an improved resistance to biotic stresses based on their function to provide protection from invasion by foreign nucleic acids, such as viruses. This natural phenomenon can be exploited to control agronomically relevant plant diseases. Recent evidence argues that this biotechnological method, called host-induced gene silencing, is effective against sucking insects, nematodes, and pathogenic fungi, as well as bacteria and viruses on their plant hosts. Here, we review recent studies which reveal the enormous potential that RNA-silencing strategies hold for providing an environmentally friendly mechanism to protect crop plants from viral diseases. Keywords: RNA silencing; Host-induced gene silencing; Spray-induced gene silencing; virus control; RNA silencing-based crop protection; GMO crops 1. Introduction Antiviral Plant Defence Responses Plant viruses are submicroscopic spherical, rod-shaped or filamentous particles which contain different kinds of genomes.