DOCSLIB.ORG

PSF: Nuclear Busy-Body Or Nuclear Facilitator?

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PSF: Nuclear Busy-Body Or Nuclear Facilitator? Advanced Review PSF: nuclear busy-body or nuclear facilitator? Christopher A. Yarosh,1 Joseph R. Iacona,2 Carol S. Lutz2 and Kristen W. Lynch1∗ PTB-associated splicing factor (PSF) is an abundant and essential nucleic acid-binding protein that participates in a wide range of gene regulatory pro- cesses and cellular response pathways. At the protein level, PSF consists of multiple domains, many of which remain poorly characterized. Although grouped in a fam- ily with the proteins p54nrb/NONO and PSPC1 based on sequence homology, PSF contains additional protein sequence not included in other family members. Con- sistently, PSF has also been implicated in functions not ascribed to p54nrb/NONO or PSPC1. Here, we provide a review of the cellular activities in which PSF has been implicated and what is known regarding the mechanisms by which PSF functions in each case. We propose that the complex domain arrangement of PSF allows for its diversity of function and integration of activities. Finally, we discuss recent evi- dence that individual activities of PSF can be regulated independently from one another through the activity of domain-specific co-factors. © 2015 The Authors. WIREs RNA published by John Wiley & Sons, Ltd. Howtocitethisarticle: WIREs RNA 2015. doi: 10.1002/wrna.1280 INTRODUCTION fully appreciate the broad importance of this protein, and much remains to be understood about how PSF TB-associated splicing factor/splicing factor carries out its many roles in DNA and RNA stability proline-glutamine rich (PSF or SFPQ), as the P and expression. names imply, was first identified as a protein required PSF belongs to a conserved family of multifunc- for pre-mRNA splicing that interacts with the splicing tional nuclear factors termed DBHS (Drosophila regulatory protein polypyrimidine tract-binding pro- behavior human splicing) proteins, which also tein (PTB).1 Cloning and sequencing of this protein includes human p54nrb (also known as NONO) also revealed it to be markedly enriched for proline and PSPC1 (paraspeckle protein component 1).2,3 All and glutamine residues.1 However, these names belie three of these DBHS proteins are conserved through- the complexity of protein domains, interacting part- out vertebrate species, while flies, worms, and yeast ners, and cellular activities that have subsequently express a single DBHS protein. DBHS proteins are been ascribed to PSF in the 20+ years since its initial defined by a core domain arrangement consisting of characterization. Indeed, we are only just beginning to tandem RNA-recognition motifs (RRMs), a ∼100 ∗Correspondence to: [email protected] amino acid coiled-coil domain, and a conserved inter- vening sequence referred to as a NONA/ParaSpeckle 1Department of Biochemistry and Biophysics, University of Penn- sylvania, Philadelphia, PA, USA (NOPS) domain. Importantly, the NOPS and RRM2 2Department of Microbiology, Biochemistry and Molecular Genet- domains mediate the formation of homodimers and ics, Rutgers Biomedical and Health Sciences-New Jersey Medical heterodimers among the DBHS proteins4 (see below). School, Newark, NJ, USA Not surprisingly, therefore, all three DHBS proteins , Conflict of interest: The authors declare no conflict of interest. often co-localize and co-purify together.5 6 © 2015 The Authors. WIREs RNA published by John Wiley & Sons, Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Advanced Review wires.wiley.com/rna In terms of subcellular localization, PSF and the other DHBS proteins can be found in the nucleoplasm and nucleolar caps as well as in paraspeckles.2,3,7 Transcription Although not completely understood, the parti- Pre-mRNA splicing 3′-end processing tioning of PSF into these various compartments may be controlled by cellular environment and/or Nuclear retention Apoptosis post-translational modifications (PTM; see Reg- of RNA PSF ulation). Of particular interest is the location of PSF in paraspeckles, as this is a definitive feature Host response to 3 DNA repair of DBHS proteins. Paraspeckles are subnuclear viral infection bodies that are often present adjacent to, but dis- Translation tinct from, speckles and are defined by the presence FIGURE 1| Cellular activities of PTB-associated splicing factor of the NEAT1 (nuclear-enriched abundant tran- (PSF). A schematic highlighting the cellular activities which PSF has thus script 1) noncoding RNA (ncRNA) and the DHBS far been reported to regulate. Black activities are those for which the proteins.3,8 Knockdown studies have shown that mechanism of PSF activity is best understood. Gray activities are those both PSF and p54nrb/NONO are required for the with less experimental support or unclear mechanism. Dotted double formation of paraspeckles, while PSPC1 is less critical arrow indicates coordination of activities through PSF. for paraspeckle formation and may localize to these structures as a consequence of the protein–protein has the potential to serve as a bridge between nuclear interactions among all the DHBS proteins.9 The processes, a critical consequence of PSF’s multifaceted structure, regulation, and function of paraspeckles existence and a theme highlighted by several studies. have been reviewed elsewhere,3,7 so are not covered Is there one cellular process for which PSF is partic- in depth here. ularly indispensible, or does the loss of PSF result in In addition to the common DHBS core, PSF cell death through partial compromise or disconnec- features additional domains (see below) that are tion of many processes simultaneously? In order to not present in p54nrb/NONO or PSPC1.2 These answer these questions, we need a better understand- PSF-specific domains confer unique functions and reg- ing of the mechanism by which PSF contributes to each ulatory sites to PSF that are not matched in the of its known activities and of how the participation of other DBHS proteins. Notably, PSF, but not the other PSF in this assortment of activities is regulated. vertebrate DBHS proteins, is essential for cellular viability. In cultured human cells, reduction of PSF expression by as little as twofold to threefold induces CELLULAR ACTIVITIES OF PSF 10,11 rapid apoptosis. Conversely, p54nrb/NONO is A confounding issue in the study of PSF is the readily knocked down with little phenotype, and fact that this protein has been implicated in such some mammalian cell types do not express detectable a wide range of cellular activities (Figure 1). To 11–13 amounts of PSPC1. In zebrafish, PSF is nec- begin to understand PSF, one must first consider essary for general cell survival and for neuronal what is known about its biochemical and cellular development, while in mice even modest depletion functions and determine which activities are clearly of PSF in thymocytes is sufficient to block T-cell direct functions of PSF, and which may be indirect 10,14 development. Moreover, somatic mutations in the consequences of other mechanisms or have been less gene encoding PSF, or gene fusion events between convincingly demonstrated. PSF and other proteins, have been linked to multi- ple diseases including autism,15 Alzheimer’s disease,16 renal cell carcinoma,17 acute myeloid and lymphoblas- Splicing tic leukemia,18,19 and prostate cancer.20 Whether the The first activity attributed to PSF was pre-mRNA expression or function of PSF is altered in these disease splicing. In 1991, Patton et al. demonstrated that states remains to be determined. a complex containing the RNA-binding protein In sum, PSF is a unique multidomain protein that PTB and an unknown splicing factor of apparent is essential to the viability of many, if not all, eukary- molecular weight of 100 kDa was required to splice otic cells. However, the precise reason PSF is required an -tropomyosin pre-mRNA substrate in nuclear for cell growth and development remains unknown. extracts.21 They went on to clone this unknown As described below, PSF has been shown to play a protein in 1993 and coined the name PSF.1 In nuclear role in many aspects of nucleic acid biology, from extract, pre-mRNA splicing requires the step-wise genome stability to RNA processing. Moreover, PSF assembly of multiple spliceosomal subunits and © 2015 The Authors. WIREs RNA published by John Wiley & Sons, Ltd. WIREs RNA Polypyrimidine tract-binding protein-associated splicing factor co-factors to form the final enzymatic spliceosome These early studies of PSF function, together complex22 (Box 1). Immunodepletion of nuclear with two decades of increased knowledge of splic- extract with antibodies to PSF was shown to block ing regulation, suggest a model in which PSF is spliceosome assembly at the earliest steps.1 These in loosely associated with the spliceosome in such a vitro experiments were interpreted to suggest that PSF way that it can impact spliceosome assembly in a had a general and essential role in early spliceosome substrate-dependent manner. Such activity is typical formation; however, with hindsight it seems likely that of proteins we now call splicing regulators, which are many PSF-co-associated proteins were also lost during broadly defined as any protein that controls alterna- immunodepletion of PSF. Moreover, it is now known tive splicing.30 PSF has recently been shown to influ- that individual pre-mRNA substrates often have dis- ence alternative splicing of both
Load more

Recommended publications
  • The Emerging Role of Ncrnas and RNA-Binding Proteins in Mitotic Apparatus Formation
    non-coding RNA Review The Emerging Role of ncRNAs and RNA-Binding Proteins in Mitotic Apparatus Formation Kei K. Ito, Koki Watanabe and Daiju Kitagawa * Department of Physiological Chemistry, Graduate School of Pharmaceutical Science, The University of Tokyo, Bunkyo, Tokyo 113-0033, Japan; [email protected] (K.K.I.); [email protected] (K.W.) * Correspondence: [email protected] Received: 11 November 2019; Accepted: 13 March 2020; Published: 20 March 2020 Abstract: Mounting experimental evidence shows that non-coding RNAs (ncRNAs) serve a wide variety of biological functions. Recent studies suggest that a part of ncRNAs are critically important for supporting the structure of subcellular architectures. Here, we summarize the current literature demonstrating the role of ncRNAs and RNA-binding proteins in regulating the assembly of mitotic apparatus, especially focusing on centrosomes, kinetochores, and mitotic spindles. Keywords: ncRNA; centrosome; kinetochore; mitotic spindle 1. Introduction Non-coding RNAs (ncRNAs) are defined as a class of RNA molecules that are transcribed from genomic DNA, but not translated into proteins. They are mainly classified into the following two categories according to their length—small RNA (<200 nt) and long non-coding RNA (lncRNA) (>200 nt). Small RNAs include traditional RNA molecules, such as transfer RNA (tRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), PIWI-interacting RNA (piRNA), and micro RNA (miRNA), and they have been studied extensively [1]. Research on lncRNA is behind that on small RNA despite that recent transcriptome analysis has revealed that more than 120,000 lncRNAs are generated from the human genome [2–4].
    [Show full text]
  • SFPQ Rescues F508del-CFTR Expression and Function in Cystic
    www.nature.com/scientificreports OPEN SFPQ rescues F508del‑CFTR expression and function in cystic fbrosis bronchial epithelial cells Parameet Kumar1,5, Dharmendra Kumar Soni1,5, Chaitali Sen1, Mads B. Larsen2, Krystyna Mazan‑Mamczarz3, Yulan Piao3, Supriyo De3, Myriam Gorospe3, Raymond A. Frizzell2 & Roopa Biswas1,4* Cystic fbrosis (CF) occurs as a result of mutations in the cystic fbrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafcking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine‑rich (SFPQ) is a multifunctional nuclear RNA‑binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafcking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del‑CFTR in CF lung epithelial cells. We fnd that the expression of SFPQ is reduced in F508del‑CFTR CF epithelial cells compared to WT‑CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del‑CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del‑CFTR by modulating several cellular signaling pathways. This is the frst report on the role of SFPQ in the regulation of expression and function of F508del‑CFTR in CF lung disease. Our fndings provide new insights into SFPQ‑mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases. Cystic fbrosis (CF) is a common life-limiting autosomal recessive genetic disease. Tis disease occurs as a result of mutations in the cystic fbrosis transmembrane conductance regulator (CFTR) gene.
    [Show full text]
  • SFPQ and NONO Suppress RNA:DNA-Hybrid-Related Telomere
    ARTICLE https://doi.org/10.1038/s41467-019-08863-1 OPEN SFPQ and NONO suppress RNA:DNA-hybrid- related telomere instability Eleonora Petti1,2,6, Valentina Buemi1,2, Antonina Zappone1,2, Odessa Schillaci1, Pamela Veneziano Broccia1,2, Roberto Dinami1,2,6, Silvia Matteoni 3, Roberta Benetti4,5 & Stefan Schoeftner1,2 In vertebrates, the telomere repeat containing long, non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres. This results in the formation of R-loop structures, replication 1234567890():,; stress and telomere instability, but also contributes to alternative lengthening of telomeres (ALT). Here, we identify the TERRA binding proteins NONO and SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. NONO and SFPQ act as heterodimers to suppress fragility and homologous recombination at telo- meres, respectively. Combining increased telomere fragility with unleashing telomere recombination upon NONO/SFPQ loss of function causes massive recombination events, involving 35% of telomeres in ALT cells. Our data identify the RNA binding proteins SFPQ and NONO as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids. 1 Genomic Stability Unit, Laboratorio Nazionale—Consorzio Interuniversitario per le Biotecnologie (LNCIB), Padriciano 99, 34149 Trieste, Italy. 2 Department of Life Sciences, Università degli Studi di Trieste, Via E. Weiss 2, 34127 Trieste, Italy. 3 Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS—Regina Elena National Cancer Institute, via Elio Chianesi 53, 00144 Rome, Italy.
    [Show full text]
  • Table S3a Table
    Table S3a C2 KEGG Geneset Genesets enriched and upregulated in responders (FDR <0.25) Genesets enriched and upregulated in non-responders (FDR <0.25) HSA04610_COMPLEMENT_AND_COAGULATION_CASCADES HSA00970_AMINOACYL_TRNA_BIOSYNTHESIS HSA04640_HEMATOPOIETIC_CELL_LINEAGE HSA05050_DENTATORUBROPALLIDOLUYSIAN_ATROPHY HSA04060_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION HSA04514_CELL_ADHESION_MOLECULES HSA04650_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY HSA04630_JAK_STAT_SIGNALING_PATHWAY HSA03320_PPAR_SIGNALING_PATHWAY HSA04080_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION HSA00980_METABOLISM_OF_XENOBIOTICS_BY_CYTOCHROME_P450 HSA00071_FATTY_ACID_METABOLISM HSA04660_T_CELL_RECEPTOR_SIGNALING_PATHWAY HSA04612_ANTIGEN_PROCESSING_AND_PRESENTATION HSA04662_B_CELL_RECEPTOR_SIGNALING_PATHWAY HSA04920_ADIPOCYTOKINE_SIGNALING_PATHWAY HSA00120_BILE_ACID_BIOSYNTHESIS HSA04670_LEUKOCYTE_TRANSENDOTHELIAL_MIGRATION HSA00641_3_CHLOROACRYLIC_ACID_DEGRADATION HSA04020_CALCIUM_SIGNALING_PATHWAY HSA04940_TYPE_I_DIABETES_MELLITUS HSA04512_ECM_RECEPTOR_INTERACTION HSA00010_GLYCOLYSIS_AND_GLUCONEOGENESIS HSA02010_ABC_TRANSPORTERS_GENERAL HSA04664_FC_EPSILON_RI_SIGNALING_PATHWAY HSA04710_CIRCADIAN_RHYTHM HSA04510_FOCAL_ADHESION HSA04810_REGULATION_OF_ACTIN_CYTOSKELETON HSA00410_BETA_ALANINE_METABOLISM HSA01040_POLYUNSATURATED_FATTY_ACID_BIOSYNTHESIS HSA00532_CHONDROITIN_SULFATE_BIOSYNTHESIS HSA04620_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY HSA04010_MAPK_SIGNALING_PATHWAY HSA00561_GLYCEROLIPID_METABOLISM HSA00053_ASCORBATE_AND_ALDARATE_METABOLISM HSA00590_ARACHIDONIC_ACID_METABOLISM
    [Show full text]
  • Sequence, Structure and Context Preferences of Human RNA
    bioRxiv preprint doi: https://doi.org/10.1101/201996; this version posted October 12, 2017. 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. Sequence, Structure and Context Preferences of Human RNA Binding Proteins Daniel Dominguez§,1, Peter Freese§,2, Maria Alexis§,2, Amanda Su1, Myles Hochman1, Tsultrim Palden1, Cassandra Bazile1, Nicole J Lambert1, Eric L Van Nostrand3,4, Gabriel A. Pratt3,4,5, Gene W. Yeo3,4,6,7, Brenton R. Graveley8, Christopher B. Burge1,9,* 1. Department of Biology, MIT, Cambridge MA 2. Program in Computational and Systems Biology, MIT, Cambridge MA 3. Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 4. Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA 5. Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA 6. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 7. Molecular Engineering Laboratory. A*STAR, Singapore 8. Department of Genetics and Genome Sciences, Institute for Systems Genomics, Univ. Connecticut Health, Farmington, CT 9. Department of Biological Engineering, MIT, Cambridge MA * Address correspondence to: [email protected] 1 of 61 bioRxiv preprint doi: https://doi.org/10.1101/201996; this version posted October 12, 2017. 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.
    [Show full text]
  • Structural Study on Apoptosis of Chronic Eosinophilic Leukemia Cells by Interaction of S100A8 with Splicing Factor, Proline and Glutamine-Rich
    pISSN 2287-5123·eISSN 2287-4445 https://doi.org/10.9729/AM.2017.47.4.233 Review Article Structural Study on Apoptosis of Chronic Eosinophilic Leukemia Cells by Interaction of S100A8 with Splicing Factor, Proline and Glutamine-Rich Yubin Won1,†, Hyosun Choi2,†, In Sik Kim2,3, Ji Young Mun1,2,* 1Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam 13135, Korea 2BK21 Plus Program, Department of Senior Healthcare, Graduate School, Eulji University, Daejeon 34824, Korea 3Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Daejeon 34824, Korea †These authors contributed equally to Chronic eosinophilic leukemia (CEL) is a myeloproliferative disease with an increased this work. number of mature eosinophils and their precursors, which results in infiltration into organs and organ enlargement. The main cause of this disease is the overexpression *Correspondence to: of tyrosine kinase. However, there is a need for alternative medication, because some Mun JY, patients are resistant to imatinib, which is a tyrosine kinase inhibitor for leukemia. Many Tel: +82-31-740-7380 studies have indicated that S100A8 and splicing factor proline and glutamine-rich (SFPQ) Fax: +82-31-740-7354 function as initiation signals of apoptosis in CEL cells. We reviewed structural studies on E-mail: [email protected] CEL cells related to S100A8 and SFPQ. Particularly, this review highlighted microscopic Received November 8, 2017 results for the study of S100A8 and SFPQ in CEL cells. Revised December 10, 2017 Accepted December 15, 2017 Key Words: SFPQ, S100A8, Microscopy, Chronic leukemia INTRODUCTION leukemia, including CEL, is the overexpression of tyrosine kinase (Demoulin & Montano-Almendras, 2012).
    [Show full text]
  • Crispri Mediated Down Regulation of SFPQ Gene Expression in Human Induced Pluripotent Stem Cells Results in Massive Cell Death
    CRISPRi mediated Down regulation of SFPQ Gene Expression in Human induced Pluripotent Stem Cells Results in Massive Cell Death Navya Lam Henry M Gunn High School Shinya Yamanaka Gladstone Institutes Samuel Perli ( [email protected] ) Gladstone Institutes Research Article Keywords: iPSCs, CRISPRi, sgRNA, SFPQ, Repression, Paraspeckles Posted Date: January 13th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-139703/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/12 Abstract CRISPR-Cas9 is widely used for targeted genome editing for a wide range of organisms. In this study, we used CRISPR interference (CRISPRi) which employs a catalytically inactive version of Cas9 (known as Dead Cas9 or dCas9) fused to KRAB a chromatin modier. Similar to Cas9, the dCas9 protein forms a complex along with single guide RNA (sgRNA) and binds desired DNA sequences in the presence of a protospacer adjacent motif (PAM). However, unlike Cas9, dCas9 doesn’t cleave the DNA sequence but can repress gene expression when fused with KRAB. The role of paraspeckles in human cell biology is relatively unknown. In this study, we used CRISPRi to investigate the role of splicing factor proline and glutamine rich (SFPQ), also known as PSF (PTB-associated splicing factor), which is a conserved and core component of paraspeckles. We designed and constructed six different sgRNAs to target different locations of the SFPQ gene in Human induced Pluripotent Stem Cells (HiPSCs). The most effective sgRNA (sgRNA #5) knocked down the expression of SFPQ up to > 99%. We also observed that the knockdown of SFPQ exhibits severe cell-death phenotype in HiPSCs.
    [Show full text]
  • Atlas Journal
    Atlas of Genetics and Cytogenetics in Oncology and Haematology Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Portal Teaching X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA Atlas Journal Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 3, Number 3, Jul-Sep 1999 Previous Issue / Next Issue Genes CBFb (subunit b of core binding factor) (16q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 286-290. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CBFbID45.html MYH11 (myosin heavy chain) (incomplete) (16p13). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 291-295. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MYH11ID43.html PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) (10q23.3). Michel Longy. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 296-300. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PTENID158.html CBLb (Cas-Br-M (murine) ecotropic retroviral transforming sequence b) (3q). Olivier Rosnet. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 301-3055. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CBLbID193.html CBLc (Cas-Br-M (murine) ecotropic retroviral transforming sequence c) (19q13.2). Olivier Rosnet. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 306-309. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CBLcID194.html CBL (Cas-Br-M (murine) ecotropic retroviral transforming sequence) (11q23-q25). Olivier Rosnet. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 310-314.
    [Show full text]
  • EBV Noncoding RNA EBER2 Interacts with Host RNA-Binding Proteins to Regulate Viral Gene Expression
    EBV noncoding RNA EBER2 interacts with host RNA- binding proteins to regulate viral gene expression Nara Leea, Therese A. Yarioa, Jessica S. Gaoa, and Joan A. Steitza,b,1 aDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06536; and bHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536 Contributed by Joan A. Steitz, February 9, 2016 (sent for review December 11, 2015; reviewed by Archa Fox and Lynne E. Maquat) Epstein–Barr virus (EBV) produces a highly abundant noncoding RNA (8, 9), knockdown of either EBER2 or PAX5 leads to diminished called EBV-encoded RNA 2 (EBER2) that interacts indirectly with the viral replication (3). host transcription factor paired box protein 5 (PAX5) to regulate viral The RNA recognition motif (RRM) is widely found in ∼1% of latent membrane protein 1/2 (LMP1/2) gene expression as well as EBV protein-coding genes in the human genome (10). This abundant lytic replication. To identify intermediary proteins, we isolated EBER2– class of proteins has been implicated in a diverse range of cellular PAX5-containing complexes and analyzed the protein components by processes, such as alternative splicing, RNA export, and regulation mass spectrometry. The top candidates include three host proteins of RNA stability (11, 12). RRM-containing proteins also execute splicing factor proline and glutamine rich (SFPQ), non-POU domain- functions in which their RNA-binding ability is not intuitively ap- containing octamer-binding protein (NONO), and RNA binding motif parent, such as transcription regulation. Several RRM-containing protein 14 (RBM14), all reported to be components of nuclear bodies proteins have been reported to carry out multiple functions (13).
    [Show full text]
  • Identification of RNA-Binding Proteins As Targetable Putative Oncogenes
    International Journal of Molecular Sciences Article Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma Jessica L. Bell 1,2,*, Sven Hagemann 1, Jessica K. Holien 3,4 , Tao Liu 2, Zsuzsanna Nagy 2,5, Johannes H. Schulte 6,7, Danny Misiak 1 and Stefan Hüttelmaier 1,* 1 Institute of Molecular Medicine, Sect. Molecular Cell Biology, Martin Luther University Halle-Wittenberg, Charles Tanford Protein Center, 06120 Halle Saale, Germany; [email protected] (S.H.); [email protected] (D.M.) 2 Children’s Cancer Institute Australia, Randwick, NSW 2031, Australia; [email protected] (T.L.); [email protected] (Z.N.) 3 St. Vincent’s Institute of Medical Research, Fitzroy, Victoria 3065, Australia; [email protected] 4 Biosciences and Food Technology, School of Science, College of Science, Engineering and Health, RMIT University, Melbourne, Victoria 3053, Australia 5 School of Women’s & Children’s Health, UNSW Sydney, Randwick, NSW 2031, Australia 6 Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany; [email protected] 7 German Consortium for Translational Cancer Research (DKTK), Partner Site Charité Berlin, 10117 Berlin, Germany * Correspondence: [email protected] (J.L.B.); [email protected] (S.H.) Received: 23 April 2020; Accepted: 14 July 2020; Published: 19 July 2020 Abstract: Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied.
    [Show full text]
  • Human SFPQ Peptide (DAG-P1971) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Human SFPQ peptide (DAG-P1971) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Antigen Description DNA- and RNA binding protein, involved in several nuclear processes. Essential pre-mRNA splicing factor required early in spliceosome formation and for splicing catalytic step II, probably as an heteromer with NONO. Binds to pre-mRNA in spliceosome C complex, and specifically binds to intronic polypyrimidine tracts. Interacts with U5 snRNA, probably by binding to a purine- rich sequence located on the 3' side of U5 snRNA stem 1b. May be involved in a pre-mRNA coupled splicing and polyadenylation process as component of a snRNP-free complex with SNRPA/U1A. The SFPQ-NONO heteromer associated with MATR3 may play a role in nuclear retention of defective RNAs. SFPQ may be involved in homologous DNA pairing; in vitro, promotes the invasion of ssDNA between a duplex DNA and produces a D-loop formation. The SFPQ-NONO heteromer may be involved in DNA unwinding by modulating the function of topoisomerase I/TOP1; in vitro, stimulates dissociation of TOP1 from DNA after cleavage and enhances its jumping between separate DNA helices. The SFPQ-NONO heteromer may be involved in DNA nonhomologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination and may stabilize paired DNA ends; in vitro, the complex strongly stimulates DNA end joining, binds directly to the DNA substrates and cooperates with the Ku70/G22P1-Ku80/XRCC5 (Ku) dimer to establish a functional preligation complex. SFPQ is involved in transcriptional regulation. Transcriptional repression is probably mediated by an interaction of SFPQ with SIN3A and subsequent recruitment of histone deacetylases (HDACs).
    [Show full text]
  • EBV Noncoding RNA EBER2 Interacts with Host RNA-Binding Proteins To
    EBV noncoding RNA EBER2 interacts with host RNA- binding proteins to regulate viral gene expression Nara Leea, Therese A. Yarioa, Jessica S. Gaoa, and Joan A. Steitza,b,1 aDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06536; and bHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536 Contributed by Joan A. Steitz, February 9, 2016 (sent for review December 11, 2015; reviewed by Archa Fox and Lynne E. Maquat) Epstein–Barr virus (EBV) produces a highly abundant noncoding RNA (8, 9), knockdown of either EBER2 or PAX5 leads to diminished called EBV-encoded RNA 2 (EBER2) that interacts indirectly with the viral replication (3). host transcription factor paired box protein 5 (PAX5) to regulate viral The RNA recognition motif (RRM) is widely found in ∼1% of latent membrane protein 1/2 (LMP1/2) gene expression as well as EBV protein-coding genes in the human genome (10). This abundant lytic replication. To identify intermediary proteins, we isolated EBER2– class of proteins has been implicated in a diverse range of cellular PAX5-containing complexes and analyzed the protein components by processes, such as alternative splicing, RNA export, and regulation mass spectrometry. The top candidates include three host proteins of RNA stability (11, 12). RRM-containing proteins also execute splicing factor proline and glutamine rich (SFPQ), non-POU domain- functions in which their RNA-binding ability is not intuitively ap- containing octamer-binding protein (NONO), and RNA binding motif parent, such as transcription regulation. Several RRM-containing protein 14 (RBM14), all reported to be components of nuclear bodies proteins have been reported to carry out multiple functions (13).
    [Show full text]