UPF1 in Nonsense-Mediated Mrna Decay and Beyond
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UTR Directs UPF1-Dependent Mrna Decay in Mammalian Cells
Downloaded from genome.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Research A GC-rich sequence feature in the 3′ UTR directs UPF1-dependent mRNA decay in mammalian cells Naoto Imamachi,1 Kazi Abdus Salam,1,3 Yutaka Suzuki,2 and Nobuyoshi Akimitsu1 1Isotope Science Center, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; 2Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8562, Japan Up-frameshift protein 1 (UPF1) is an ATP-dependent RNA helicase that has essential roles in RNA surveillance and in post- transcriptional gene regulation by promoting the degradation of mRNAs. Previous studies revealed that UPF1 is associated with the 3′ untranslated region (UTR) of target mRNAs via as-yet-unknown sequence features. Herein, we aimed to identify characteristic sequence features of UPF1 targets. We identified 246 UPF1 targets by measuring RNA stabilization upon UPF1 depletion and by identifying mRNAs that associate with UPF1. By analyzing RNA footprint data of phosphorylated UPF1 and two CLIP-seq data of UPF1, we found that 3′ UTR but not 5′ UTRs or open reading frames of UPF1 targets have GC-rich motifs embedded in high GC-content regions. Reporter gene experiments revealed that GC-rich motifs in UPF1 targets were indispensable for UPF1-mediated mRNA decay. These findings highlight the important features of UPF1 target 3′ UTRs. [Supplemental material is available for this article.] RNA degradation plays a central role in the RNA surveillance ma- degradation (Unterholzner and Izaurralde 2004), respectively. chinery for aberrant mRNAs and the post-transcriptional regula- Thus, UPF1 plays a central role in the NMD pathway. -
IP6K1 Upregulates the Formation of Processing Bodies by Promoting Proteome Remodeling on the Mrna Cap
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.13.199828; this version posted July 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. IP6K1 upregulates the formation of processing bodies by promoting proteome remodeling on the mRNA cap Akruti Shah1,2 and Rashna Bhandari1* 1Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad 500039, India. 2Graduate studies, Manipal Academy of Higher Education, Manipal 576104, India. *Correspondence to Rashna Bhandari; Email: [email protected] Running title: IP6K1 promotes mRNA turnover to induce P-bodies ORCID IDs Akruti Shah - 0000-0001-9557-4952 Rashna Bhandari - 0000-0003-3101-0204 This PDF file includes: Main Text Figures 1 to 6 Keywords mRNA decay/mRNA metabolism/P-bodies/translation suppression 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.13.199828; this version posted July 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Inositol hexakisphosphate kinases (IP6Ks) are ubiquitously expressed small molecule kinases that catalyze the conversion of the inositol phosphate IP6 to 5-IP7. IP6Ks have been reported to influence cellular functions by protein-protein interactions independent of their enzymatic activity. -
Human Nonsense-Mediated RNA Decay Initiates Widely by Endonucleolysis and Targets Snorna Host Genes
Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes Søren Lykke-Andersen,1,4 Yun Chen,2,4 Britt R. Ardal,1 Berit Lilje,2 Johannes Waage,2,3 Albin Sandelin,2 and Torben Heick Jensen1 1Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University, Aarhus DK-8000, Denmark; 2The Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen DK-2200, Denmark Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 59–39 decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent. We also show that a large proportion of genes hosting snoRNAs in their introns produce considerable amounts of NMD-sensitive splice variants, indicating that these RNAs are merely by-products of a primary snoRNA production process. Additionally, transcripts from genes encoding multiple snoRNAs often yield alternative transcript isoforms that allow for differential expression of individual coencoded snoRNAs. Based on our findings, we hypothesize that snoRNA host genes need to be highly transcribed to accommodate high levels of snoRNA production and that the expression of individual snoRNAs and their cognate spliced RNA can be uncoupled via alternative splicing and NMD. -
Crystal Structure of the UPF2-Interacting Domain of Nonsense-Mediated Mrna Decay Factor UPF1
JOBNAME: RNA 12#10 2006 PAGE: 1 OUTPUT: Friday September 8 11:24:46 2006 csh/RNA/122854/rna1776 Downloaded from rnajournal.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Crystal structure of the UPF2-interacting domain of nonsense-mediated mRNA decay factor UPF1 JAN KADLEC, DELPHINE GUILLIGAY, RAIMOND B. RAVELLI, and STEPHEN CUSACK European Molecular Biology Laboratory, Grenoble Outstation, BP 181, 38042 Grenoble Cedex 9, France ABSTRACT UPF1 is an essential eukaryotic RNA helicase that plays a key role in various mRNA degradation pathways, notably nonsense- mediated mRNA decay (NMD). In combination with UPF2 and UPF3, it forms part of the surveillance complex that detects mRNAs containing premature stop codons and triggers their degradation in all organisms studied from yeast to human. We describe the 3 A˚ resolution crystal structure of the highly conserved cysteine–histidine-rich domain of human UPF1 and show that it is a unique combination of three zinc-binding motifs arranged into two tandem modules related to the RING-box and U-box domains of ubiquitin ligases. This UPF1 domain interacts with UPF2, and we identified by mutational analysis residues in two distinct conserved surface regions of UPF1 that mediate this interaction. UPF1 residues we identify as important for the interaction with UPF2 are not conserved in UPF1 homologs from certain unicellular parasites that also appear to lack UPF2 in their genomes. Keywords: nonsense-mediated mRNA decay; NMD; surveillance complex; UPF1; X-ray crystallography INTRODUCTION from the mRNA. If, however, translation terminates at a PTC upstream of an EJC, UPF2 associated with a down- Nonsense-mediated mRNA decay (NMD) is an mRNA stream EJC can be bound by UPF1 that is recruited to the degradation pathway that detects and eliminates aberrant terminating ribosome within the so-called SURF complex, coding transcripts containing premature termination codons which also includes the translation release factors eRF1 and (PTC) originating from nonsense or frameshift mutations. -
A Genome-Wide Association Study of a Coronary Artery Disease Risk Variant
Journal of Human Genetics (2013) 58, 120–126 & 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13 www.nature.com/jhg ORIGINAL ARTICLE A genome-wide association study of a coronary artery diseaseriskvariant Ji-Young Lee1,16, Bok-Soo Lee2,16, Dong-Jik Shin3,16, Kyung Woo Park4,16, Young-Ah Shin1, Kwang Joong Kim1, Lyong Heo1, Ji Young Lee1, Yun Kyoung Kim1, Young Jin Kim1, Chang Bum Hong1, Sang-Hak Lee3, Dankyu Yoon5, Hyo Jung Ku2, Il-Young Oh4, Bong-Jo Kim1, Juyoung Lee1, Seon-Joo Park1, Jimin Kim1, Hye-kyung Kawk1, Jong-Eun Lee6, Hye-kyung Park1, Jae-Eun Lee1, Hye-young Nam1, Hyun-young Park7, Chol Shin8, Mitsuhiro Yokota9, Hiroyuki Asano10, Masahiro Nakatochi11, Tatsuaki Matsubara12, Hidetoshi Kitajima13, Ken Yamamoto13, Hyung-Lae Kim14, Bok-Ghee Han1, Myeong-Chan Cho15, Yangsoo Jang3,17, Hyo-Soo Kim4,17, Jeong Euy Park2,17 and Jong-Young Lee1,17 Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. -
The Origins and Consequences of UPF1 Variants in Pancreatic Adenosquamous Carcinoma
bioRxiv preprint doi: https://doi.org/10.1101/2020.08.14.248864; this version posted August 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma Jacob T. Polaski1,2, Dylan B. Udy1,2,3, Luisa F. Escobar-Hoyos4,5,6, Gokce Askan4, Steven D. Leach4,5,7,8, Andrea Ventura9, Ram Kannan9,†, and Robert K. Bradley1,2,† 1Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA 2Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA 3Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, 98195, USA 4David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA 5Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA 6Department of Pathology, Stony Brook University, New York, New York 11794, USA 7Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA 8Dartmouth Norris Cotton Cancer Center, Lebanon, New Hampshire 03766, USA 9Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065 †Correspondence: [email protected], [email protected] Keywords: UPF1, pancreatic adenosquamous carcinoma, cancer genomics bioRxiv preprint doi: https://doi.org/10.1101/2020.08.14.248864; this version posted August 14, 2020. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Uttrykking Final Ph[1].D THESIS TUYEN 27.10.06
Nuclear Receptor Coregulators Role of Protein-Protein Interactions and cAMP/PKA Signaling Tuyen Thi Van Hoang Dissertation for the degree philosophiae doctor (PhD) at the University of Bergen October 2006 2 TABLE OF CONTENTS SCIENTIFIC ENVIRONMENTS.............................................................................................. 5 ACKNOWLEDGEMENTS ....................................................................................................... 7 LIST OF PAPERS...................................................................................................................... 9 ABBREVIATIONS.................................................................................................................. 11 PREFACE ................................................................................................................................ 13 INTRODUCTION.................................................................................................................... 15 1. Nuclear receptors ........................................................................................................... 15 1.1. Functional and structural domains ............................................................................ 15 1.2. Subfamilies and activation mechanisms ................................................................... 15 1.3. Steroidogenic factor-1............................................................................................... 19 1.3.1. Functional and structural domains .................................................................... -
Chain Gene Induced by GM-CSF Β Receptor Regulation of Human High-Affinity Ige Molecular Mechanisms for Transcriptional
Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF This information is current as Kyoko Takahashi, Natsuko Hayashi, Shuichi Kaminogawa of September 23, 2021. and Chisei Ra J Immunol 2006; 177:4605-4611; ; doi: 10.4049/jimmunol.177.7.4605 http://www.jimmunol.org/content/177/7/4605 Downloaded from References This article cites 39 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/177/7/4605.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 23, 2021 *average 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor -Chain Gene Induced by GM-CSF1 Kyoko Takahashi,*† Natsuko Hayashi,*‡ Shuichi Kaminogawa,† and Chisei Ra2* The -chain of the high-affinity receptor for IgE (FcRI) plays an important role in regulating activation of FcRI-expressing cells such as mast cells in allergic reactions. -
Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins
Biomolecules 2015, 5, 1441-1466; doi:10.3390/biom5031441 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Article Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins Rebecca Bish 1,†, Nerea Cuevas-Polo 1,†, Zhe Cheng 1, Dolores Hambardzumyan 2, Mathias Munschauer 3, Markus Landthaler 3 and Christine Vogel 1,* 1 Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, USA; E-Mails: [email protected] (R.B.); [email protected] (N.C.-P.); [email protected] (Z.C.) 2 The Cleveland Clinic, Department of Neurosciences, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA; E-Mail: [email protected] 3 RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Robert-Rössle-Str. 10, Berlin 13092, Germany; E-Mails: [email protected] (M.M.); [email protected] (M.L.) † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-212-998-3976; Fax: +1-212-995-4015. Academic Editor: André P. Gerber Received: 10 May 2015 / Accepted: 15 June 2015 / Published: 15 July 2015 Abstract: DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and mass spectrometry. Using DDX6 as bait, we identify a high-confidence and high-quality set of protein interaction partners which are enriched for functions in RNA metabolism and ribosomal proteins. -
Germ Granule-Mediated RNA Regulation in Male Germ Cells
REPRODUCTIONREVIEW Germ granule-mediated RNA regulation in male germ cells Tiina Lehtiniemi and Noora Kotaja Institute of Biomedicine, University of Turku, Turku, Finland Correspondence should be addressed to N Kotaja; Email: [email protected] Abstract Germ cells have exceptionally diverse transcriptomes. Furthermore, the progress of spermatogenesis is accompanied by dramatic changes in gene expression patterns, the most drastic of them being near-to-complete transcriptional silencing during the final steps of differentiation. Therefore, accurate RNA regulatory mechanisms are critical for normal spermatogenesis. Cytoplasmic germ cell-specific ribonucleoprotein (RNP) granules, known as germ granules, participate in posttranscriptional regulation in developing male germ cells. Particularly, germ granules provide platforms for the PIWI-interacting RNA (piRNA) pathway and appear to be involved both in piRNA biogenesis and piRNA-targeted RNA degradation. Recently, other RNA regulatory mechanisms, such as the nonsense-mediated mRNA decay pathway have also been associated to germ granules providing new exciting insights into the function of germ granules. In this review article, we will summarize our current knowledge on the role of germ granules in the control of mammalian male germ cell’s transcriptome and in the maintenance of fertility. Reproduction (2018) 155 R77–R91 Introduction then rapidly undergo the second meiotic division (meiosis II) resulting in haploid spermatids. The final Spermatogenesis is a highly specialized process that phase of spermatogenesis is haploid differentiation aims to transmit correct paternal genetic and epigenetic (spermiogenesis), which includes dramatic information to the next generation. At the embryonic morphological changes through which spermatozoa stage, the mammalian germ cell lineage is specified reach their dynamic sleek shape (Fig.