DOCSLIB.ORG

Chromosomal Translocations in NK-Cell Lymphomas Originate from Inter-Chromosomal Contacts of Active Rdna Clusters Possessing Hot Spots of Dsbs

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chromosomal Translocations in NK-Cell Lymphomas Originate from Inter-Chromosomal Contacts of Active Rdna Clusters Possessing Hot Spots of Dsbs cancers Article Chromosomal Translocations in NK-Cell Lymphomas Originate from Inter-Chromosomal Contacts of Active rDNA Clusters Possessing Hot Spots of DSBs Nickolai A. Tchurikov 1,*, Leonid A. Uroshlev 2, Elena S. Klushevskaya 1 , Ildar R. Alembekov 1, Maria A. Lagarkova 3,4 , Galina I. Kravatskaya 1, Vsevolod Y. Makeev 1,2,5 and Yuri V. Kravatsky 1 1 Engelhardt Institute of Molecular Biology Russian Academy of Sciences, 119334 Moscow, Russia; [email protected] (E.S.K.); [email protected] (I.R.A.); [email protected] (G.I.K.); [email protected] (V.Y.M.); [email protected] (Y.V.K.) 2 Vavilov Institute of General Genetics Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] 3 Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, 119435 Moscow, Russia; [email protected] 4 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, 119435 Moscow, Russia 5 Moscow Institute of Physics and Technology, State University, 141700 Dolgoprudny, Russia * Correspondence: [email protected]; Tel.: +7-499-135-9753 Simple Summary: There are nine DSB hot spots located in the non-transcribed spacer of human Citation: Tchurikov, N.A.; Uroshlev, rDNA units. Circular chromosome conformation capture data indicate that the rDNA clusters often L.A.; Klushevskaya, E.S.; Alembekov, shape contact with a specific set of chromosomal regions containing genes controlling differentiation I.R.; Lagarkova, M.A.; Kravatskaya, and cancer, and often possessing the DSB hot spots. The data suggest a mechanism for rDNA- G.I.; Makeev, V.Y.; Kravatsky, Y.V. mediated translocation, and some of them could lead to tumorigenesis. Here, we searched for Chromosomal Translocations in translocations in which rDNA clusters are involved. WGS data of normal T cells and NK-cell NK-Cell Lymphomas Originate from lymphomas from the same individuals were used. We revealed numerous translocations in which Inter-Chromosomal Contacts of rDNA units are involved. The sites of these translocations in normal T cells and in the lymphomas Active rDNA Clusters Possessing Hot Spots of DSBs. Cancers 2021, 13, 3889. were mostly different, but occurred at about the same frequency in both cell types. We conclude that https://doi.org/10.3390/ oncogenic translocations lead to dysregulation of a specific set of genes controlling development. cancers13153889 Abstract: Endogenous hot spots of DNA double-strand breaks (DSBs) are tightly linked with tran- Academic Editor: Thomas Ried scription patterns and cancer. There are nine hot spots of DSBs (denoted Pleiades) in human rDNA units that are located exclusively inside the intergenic spacer (IGS). Profiles of Pleiades coincide with Received: 6 July 2021 the profiles of γ-H2AX, suggesting a high level of in vivo breakage inside rDNA genes. The data Accepted: 30 July 2021 were confirmed by microscopic observation of the largest γ-H2AX foci inside nucleoli in interphase Published: 2 August 2021 chromosomes. Circular chromosome conformation capture (4C) data indicate that the rDNA units often make contact with a specific set of chromosomal regions containing genes that are involved Publisher’s Note: MDPI stays neutral in differentiation and cancer. Interestingly, these regions also often possess hot spots of DSBs that with regard to jurisdictional claims in provide the potential for Robertsonian and oncogenic translocations. In this study, we searched for published maps and institutional affil- translocations in which rDNA clusters are involved. The whole genome sequence (WGS) data of iations. normal T cells and NK-cell lymphomas from the same individuals revealed numerous transloca- tions in which Pleiades were involved. The sites of these translocations in normal T cells and in the lymphomas were mostly different, although there were also some common sites. The genes at translocations in normal cells and in lymphomas are associated with predominantly non-overlapping Copyright: © 2021 by the authors. lists of genes that are depleted with silenced genes. Our data indicate that rDNA-mediated transloca- Licensee MDPI, Basel, Switzerland. tions occur at about the same frequency in the normal T cells and NK-lymphoma cells but differ at This article is an open access article distributed under the terms and particular sites that correspond to open chromatin. We conclude that oncogenic translocations lead conditions of the Creative Commons to dysregulation of a specific set of genes controlling development. In normal T cells and in NK cells, Attribution (CC BY) license (https:// there are hot spots of translocations at sites possessing strong H3K27ac marks. The data indicate that creativecommons.org/licenses/by/ Pleiades are involved in rDNA-mediated translocation. 4.0/). Cancers 2021, 13, 3889. https://doi.org/10.3390/cancers13153889 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3889 2 of 18 Keywords: NK-cell lymphomas; T cells; rDNA genes; inter-chromosomal contacts; 4C; translocations 1. Introduction Chromosomal translocations are a physiologic mechanism of DNA recombination in germline cells and in lymphocyte development. Although these mechanisms have been studied for several decades, they are still not fully understood. Chromosomal translocations are common in cancers and more frequently occur between neighboring chromosomal regions [1,2]. As a result, some translocations lead to the formation of oncogenic fusion proteins or to the activation of oncogenes by the altered regulatory regions [3,4]. Ribosomal DNA (rDNA) genes are the most fragile regions in the human genome and possess nine hot spots of DSBs, each of which is about 50–100 bp in length and are denoted “Pleiades” [5,6]. Additionally, it was demonstrated by the 4C (circular chromosome conformation capture) approach that rDNA clusters shape contacts with different chromosomal regions and are involved in the epigenetic regulation of genes that are highly associated with differentiation and cancer [7]. Interestingly, rDNA-contacting sites often possess hot spots of DSBs. rDNA clusters also make frequent contacts with pericentromeric regions and regions possessing stretches of 5–50 kb that contain H3K27ac marks [5]. Therefore, Pleiades may be responsible for Robertsonian translocations, in which rDNA-containing chromosomes are necessarily involved via their broken pericentromeric regions [5]. These data indicate that rDNA genes are a candidate for mediating chromosomal translocations in normal and cancer cells. Here, we investigated whether rDNA genes are involved in chromosomal translocations by searching for rDNA-mediated translocations in normal T cells and in natural killer (NK)-cell lymphomas from the same individuals. Natural killer cells play an important role in the innate immune system that controls several types of tumors and infections [8]. NK cells, along with B and T lymphocytes, belong to a group of innate lymphoid cells that differentiate from a common lymphoid progenitor. NK cells are closely related to T cells and can lyse target cells without prior sensitization. Our data indicate that active rDNA clusters are involved in translocations in both types of cells, particularly in regions with actively transcribed genes, but the spectra of the target genes in these cell types differ. The same rDNA-mediated hot spots of translocations are found in normal and cancer cells corresponding to the hot spots of inter-chromosomal contacts of nucleoli within specific genomic regions. 2. Materials and Methods 2.1. Determination of rDNA-Mediated Translocation Sites in Paired-End WGS Reads We used the following procedure to find translocations. The data from the European Genome Archive [9] were analyzed. The NK-cell lymphoma dataset (EGAD00001003271) was selected (102 matched-sample pairs, read length 100 bp, average amplicon length 300 bp). Each pair of matched samples contained samples of cancer cells (NK-cell lym- phoma) and control cells (T cells) from the same donor. Paired-ended sequencing was conducted for all samples using the Illumina Genome Analyzer IIx and Illumina HiSeq 2000 resulting in a pair of FASTQ files for each sample, one file (L1) contained left terminal reads for each amplicon, and the other file (L2) contained the right terminal reads. Then, we searched for leading or anchor sequences corresponding to rDNA stretches (Table1) located before a hot spot of DSBs in the samples. We required an exact match between the read and the leading sequence. Leading sequences were analyzed in both the left and right fragment termini (reads indexed as R1 and R2, respectively). For each leader sequence, all reads containing this sequence were stored in a separate FASTQ file. We applied the grep utility to search for leading sequences. Cancers 2021, 13, 3889 3 of 18 Table 1. rDNA sequences (anchors) used for searching for rDNA-mediated translocations and the detected frequencies of the translocations in T cells and NK-cell lymphomas. Numbering in rDNA Unit Average Translocation Number Average Translocation Number in NK Anchors Sequences, 50–30 (Accession # U13369.1) in T Cells (102 Samples) Cells Lymphomas (102 Samples) GCAGTGCGGTGGCGCGATCTTGGCTCACCGCAA R1 19,641–19,710 575.4 430.2 CCTCTGCCTCCCGGTTTCAAGCGATTCTCCTGCATCG CCTATTTTCAGTAGAGACGGGGTTTCTCCACGTTG R2 21,261–21,330 829.6 881.9 GCCACGCTGGTCTCGAACTCCTGACCTCAAATGAT CTACTCGGGAGGCTGGGGTGGAAGAATTGCTTG R3 21,801–21,860 2015.5 2384.0 AACCTGGCAGGCGGAGGCTGCAGTGAC
Load more

Recommended publications
  • 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.
    [Show full text]
  • DIPPER, a Spatiotemporal Proteomics Atlas of Human Intervertebral Discs
    TOOLS AND RESOURCES DIPPER, a spatiotemporal proteomics atlas of human intervertebral discs for exploring ageing and degeneration dynamics Vivian Tam1,2†, Peikai Chen1†‡, Anita Yee1, Nestor Solis3, Theo Klein3§, Mateusz Kudelko1, Rakesh Sharma4, Wilson CW Chan1,2,5, Christopher M Overall3, Lisbet Haglund6, Pak C Sham7, Kathryn Song Eng Cheah1, Danny Chan1,2* 1School of Biomedical Sciences, , The University of Hong Kong, Hong Kong; 2The University of Hong Kong Shenzhen of Research Institute and Innovation (HKU-SIRI), Shenzhen, China; 3Centre for Blood Research, Faculty of Dentistry, University of British Columbia, Vancouver, Canada; 4Proteomics and Metabolomics Core Facility, The University of Hong Kong, Hong Kong; 5Department of Orthopaedics Surgery and Traumatology, HKU-Shenzhen Hospital, Shenzhen, China; 6Department of Surgery, McGill University, Montreal, Canada; 7Centre for PanorOmic Sciences (CPOS), The University of Hong Kong, Hong Kong Abstract The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity *For correspondence: and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising [email protected] 94 genome-wide profiles from 17 individuals. To begin with, protein modules defining key †These authors contributed directional trends spanning the lateral and anteroposterior axes were derived from high-resolution equally to this work spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific Present address: ‡Department profiles of regulatory activities
    [Show full text]
  • Genetic Mutations in RNA-Binding Proteins and Their Roles In
    Hum Genet DOI 10.1007/s00439-017-1830-7 REVIEW Genetic mutations in RNA‑binding proteins and their roles in ALS Katannya Kapeli1 · Fernando J. Martinez2 · Gene W. Yeo1,2,3 Received: 1 April 2017 / Accepted: 17 July 2017 © The Author(s) 2017. This article is an open access publication Abstract Mutations in genes that encode RNA-binding revealed that two-thirds of RBPs are expressed in a cell- proteins (RBPs) have emerged as critical determinants of type specifc manner (McKee et al. 2005). This specialized neurological diseases, especially motor neuron disorders expression of RBPs is thought to maintain a diverse gene such as amyotrophic lateral sclerosis (ALS). RBPs are expression profle to support the varied and complex func- involved in all aspects of RNA processing, controlling the tions of neurons. An increasing number of RBPs are being life cycle of RNAs from synthesis to degradation. Hallmark recognized as causal drivers or associated with neurological features of RBPs in neuron dysfunction include misregu- diseases (Polymenidou et al. 2012; Belzil et al. 2013; Nuss- lation of RNA processing, mislocalization of RBPs to the bacher et al. 2015), which reinforces the importance of RBPs cytoplasm, and abnormal aggregation of RBPs. Much pro- in maintaining normal physiology in the nervous system. gress has been made in understanding how ALS-associated Mutations in genes that encode RBPs have been observed mutations in RBPs drive pathogenesis. Here, we focus on in patients with motor neuron disorders such as amyotrophic several key RBPs involved in ALS—TDP-43, HNRNP A2/ lateral sclerosis (ALS), spinal muscular atrophy (SMA), B1, HNRNP A1, FUS, EWSR1, and TAF15—and review multisystem proteinopathy (MSP) and frontotemporal lobar our current understanding of how mutations in these proteins degeneration (FTLD).
    [Show full text]
  • Hnrnp A/B Proteins: an Encyclopedic Assessment of Their Roles in Homeostasis and Disease
    biology Review hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease Patricia A. Thibault 1,2 , Aravindhan Ganesan 3, Subha Kalyaanamoorthy 4, Joseph-Patrick W. E. Clarke 1,5,6 , Hannah E. Salapa 1,2 and Michael C. Levin 1,2,5,6,* 1 Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada; [email protected] (P.A.T.); [email protected] (J.-P.W.E.C.); [email protected] (H.E.S.) 2 Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK S7N 0X8, Canada 3 ArGan’s Lab, School of Pharmacy, Faculty of Science, University of Waterloo, Waterloo, ON N2L 3G1, Canada; [email protected] 4 Department of Chemistry, Faculty of Science, University of Waterloo, Waterloo, ON N2L 3G1, Canada; [email protected] 5 Department of Health Sciences, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada 6 Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada * Correspondence: [email protected] Simple Summary: The hnRNP A/B family of proteins (comprised of A1, A2/B1, A3, and A0) contributes to the regulation of the majority of cellular RNAs. Here, we provide a comprehensive overview of what is known of each protein’s functions, highlighting important differences between them. While there is extensive information about A1 and A2/B1, we found that even the basic Citation: Thibault, P.A.; Ganesan, A.; functions of the A0 and A3 proteins have not been well-studied.
    [Show full text]
  • RNA-Binding Proteins and the Complex Pathophysiology of ALS
    International Journal of Molecular Sciences Review RNA-Binding Proteins and the Complex Pathophysiology of ALS Wanil Kim 1,†, Do-Yeon Kim 2,* and Kyung-Ha Lee 1,* 1 Division of Cosmetic Science and Technology, Daegu Haany University, Hanuidae-ro 1, Gyeongsan, Gyeongbuk 38610, Korea; [email protected] 2 Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea * Correspondence: [email protected] (D.-Y.K.); [email protected] (K.-H.L.); Tel.: +82-53-660-6880 (D.-Y.K.); +82-53-819-7743 (K.-H.L.) † Current Address: Department of Biochemistry, College of Medicine, Gyeongsang National University, Jinju 52828, Korea. Abstract: Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease- causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane- less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS.
    [Show full text]
  • Autoantibodies Targeting TLR and SMAD Pathways Define New
    Journal of Autoimmunity xxx (2018) 1e12 Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm Autoantibodies targeting TLR and SMAD pathways define new subgroups in systemic lupus erythematosus ** Myles J. Lewis a, , Michael B. McAndrew b, Colin Wheeler b, Nicholas Workman b, Pooja Agashe b, Jens Koopmann c, Ezam Uddin b, David L. Morris d, Lu Zou a, * Richard Stark b, John Anson b, Andrew P. Cope e, Timothy J. Vyse d, a Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK b Oxford Gene Technology, Unit 15, Oxford Industrial Park, Yarnton, Oxfordshire, OX5 1QU, UK c MedImmune, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK d Department of Medical and Molecular Genetics, King's College London, London, SE1 9RT, UK e Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London, London, SE1 9RT, UK article info abstract Article history: Objectives: The molecular targets of the vast majority of autoantibodies in systemic lupus erythematosus Received 8 January 2018 (SLE) are unknown. We set out to identify novel autoantibodies in SLE to improve diagnosis and identify Received in revised form subgroups of SLE individuals. 20 February 2018 Methods: A baculovirus-insect cell expression system was used to create an advanced protein microarray Accepted 23 February 2018 with 1543 full-length human proteins expressed with a biotin carboxyl carrier protein (BCCP) folding tag, Available online xxx to enrich for correctly folded proteins.
    [Show full text]
  • Specific Heterozygous Frameshift Variants in Hnrnpa2b1 Cause Early-Onset Oculopharyngeal Muscular Dystrophy
    medRxiv preprint doi: https://doi.org/10.1101/2021.04.08.21254942; this version posted April 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Specific heterozygous frameshift variants in hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy Hong Joo Kim1*, Payam Mohassel2*, Sandra Donkervoort2, Lin Guo3, 4, Kevin O’Donovan1, Maura Coughlin1, Xaviere Lornage5, Nicola Foulds6, Simon R. Hammans7, A. Reghan Foley2, Charlotte M. Fare3, Alice F. Ford3, Masashi Ogasawara8,9, Aki Sato10, Aritoshi Iida9, Pinki Munot11, Gautam Ambegaonkar12, Rahul Phadke13, Dominic G O’Donovan14, Rebecca Buchert15, Mona Grimmel15, Ana Töpf16, Irina T. Zaharieva11, Lauren Brady17, Ying Hu2, Thomas E. Lloyd18, Andrea Klein19,20, Maja Steinlin19, Alice Kuster21, Sandra Mercier22, Pascale Marcorelles23, Yann Péréon24, Emmanuelle Fleurence25, Adnan Manzur11, Sarah Ennis26, Rosanna Upstill-Goddard26, Luca Bello27, Cinzia Bertolin28, Elena Pegoraro27, Leonardo Salviati28, Courtney E. French29, Andriy Shatillo30, F Lucy Raymond31, Tobias Haack15, Susana Quijano-Roy32, Johann Böhm5, Isabelle Nelson33, Tanya Stojkovic34, Teresinha Evangelista35, Volker Straub16, Norma B. Romero34,35, Jocelyn Laporte5, Francesco Muntoni11, Ichizo Nishino8,9, Mark A. Tarnopolsky17, James Shorter3, J. Paul Taylor1,36#, Carsten G. Bönnemann2# 1. Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA 2. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA 3. Department of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 4. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
    [Show full text]
  • Characterization of HNRNPA1 Mutations Defines Diversity in Pathogenic Mechanisms and Clinical Presentation
    RESEARCH ARTICLE Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation Danique Beijer,1,2 Hong Joo Kim,3 Lin Guo,4,5 Kevin O’Donovan,3 Inès Mademan,1,2 Tine Deconinck,6 Kristof Van Schil,6 Charlotte M. Fare,4 Lauren E. Drake,4 Alice F. Ford,4 Andrzej Kochański,7 Dagmara Kabzińska,7 Nicolas Dubuisson,8 Peter Van den Bergh,8 Nicol C. Voermans,9 Richard J.L.F. Lemmers,10 Silvère M. van der Maarel,10 Devon Bonner,11 Jacinda B. Sampson,11 Matthew T. Wheeler,11 Anahit Mehrabyan,12 Steven Palmer,12 Peter De Jonghe,1,2,13 James Shorter,4 J. Paul Taylor,3,14 and Jonathan Baets1,2,13 1Translational Neurosciences, Faculty of Medicine and Health Sciences, and 2Laboratory for Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium. 3Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. 4Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 5Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.6 Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium. 7Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. 8Neuromuscular Reference Centre, University Hospitals St-Luc, University of Louvain, Brussels, Belgium. 9Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands. 10Human Genetics Department, Leiden University Medical Center, Netherlands. 11Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA. 12Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
    [Show full text]
  • Proteomic Analysis Reveals That MAEL, a Component of Nuage, Interacts with Stress Granule Proteins in Cancer Cells
    342 ONCOLOGY REPORTS 31: 342-350, 2014 Proteomic analysis reveals that MAEL, a component of nuage, interacts with stress granule proteins in cancer cells LIQIN YUAN1, YUZHONG XIAO2, QIUZHI ZHOU2, DONGMEI YUAN2, BAIPING WU1, GANNONG CHEN1 and JIANLIN ZHOU2 1Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011; 2Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, P.R. China Received September 24, 2013; Accepted October 21, 2013 DOI: 10.3892/or.2013.2836 Abstract. The Maelstrom (MAEL) gene is a cancer-testis (or Introduction cancer-germline) gene, which is predominantly expressed in germline cells under normal conditions, but is aberrantly The Maelstrom (MAEL) gene was first identified inDrosophila expressed in a range of human cancer cells. In germline cells, (1). It plays a role in the establishment of oocyte polarity by MAEL is found predominantly in the nuage, where it plays acting in the positioning of mRNA and the microtubule- an essential role in piRNA biogenesis and piRNA-mediated organizing center (MTOC) in early oocytes (1,2). Drosophila silencing of transposons. However, the role of MAEL in cancer maelstrom protein co-localizes with Vasa and Aubergine in the has not been elucidated. We performed immunoprecipitation nuage (3), a germline-unique perinuclear structure that serves and Nano-LC-MS/MS analysis to investigate the interactome of as a platform for PIWI-interacting RNA (piRNA) biogenesis MAEL, and identified 14 components of stress granules (SGs) as and piRNA-dependent silencing of transposons and some other potential binding partners of MAEL in MDA-MB-231 human harmful selfish elements (4,5).
    [Show full text]
  • RNA-Binding Proteins with Prion-Like Domains in Health and Disease
    Biochemical Journal (2017) 474 1417–1438 DOI: 10.1042/BCJ20160499 Review Article RNA-binding proteins with prion-like domains in health and disease Alice Ford Harrison1,2 and James Shorter1,2 1Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A. and 2Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, U.S.A. Correspondence: James Shorter ( [email protected]) Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA- binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribo- nucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via path- ology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.
    [Show full text]
  • Lupus Nephritis Supp Table 5
    Supplementary Table 5 : Transcripts and DAVID pathways correlating with the expression of CD4 in lupus kidney biopsies Positive correlation Negative correlation Transcripts Pathways Transcripts Pathways Identifier Gene Symbol Correlation coefficient with CD4 Annotation Cluster 1 Enrichment Score: 26.47 Count P_Value Benjamini Identifier Gene Symbol Correlation coefficient with CD4 Annotation Cluster 1 Enrichment Score: 3.16 Count P_Value Benjamini ILMN_1727284 CD4 1 GOTERM_BP_FAT translational elongation 74 2.50E-42 1.00E-38 ILMN_1681389 C2H2 zinc finger protein-0.40001984 INTERPRO Ubiquitin-conjugating enzyme/RWD-like 17 2.00E-05 4.20E-02 ILMN_1772218 HLA-DPA1 0.934229063 SP_PIR_KEYWORDS ribosome 60 2.00E-41 4.60E-39 ILMN_1768954 RIBC1 -0.400186083 SMART UBCc 14 1.00E-04 3.50E-02 ILMN_1778977 TYROBP 0.933302249 KEGG_PATHWAY Ribosome 65 3.80E-35 6.60E-33 ILMN_1699190 SORCS1 -0.400223681 SP_PIR_KEYWORDS ubl conjugation pathway 81 1.30E-04 2.30E-02 ILMN_1689655 HLA-DRA 0.915891173 SP_PIR_KEYWORDS protein biosynthesis 91 4.10E-34 7.20E-32 ILMN_3249088 LOC93432 -0.400285215 GOTERM_MF_FAT small conjugating protein ligase activity 35 1.40E-04 4.40E-02 ILMN_3228688 HLA-DRB1 0.906190291 SP_PIR_KEYWORDS ribonucleoprotein 114 4.80E-34 6.70E-32 ILMN_1680436 CSH2 -0.400299744 SP_PIR_KEYWORDS ligase 54 1.50E-04 2.00E-02 ILMN_2157441 HLA-DRA 0.902996561 GOTERM_CC_FAT cytosolic ribosome 59 3.20E-33 2.30E-30 ILMN_1722755 KRTAP6-2 -0.400334007 GOTERM_MF_FAT acid-amino acid ligase activity 40 1.60E-04 4.00E-02 ILMN_2066066 HLA-DRB6 0.901531942 SP_PIR_KEYWORDS
    [Show full text]
  • Autoantibody Signatures Involving Glycolysis and Splicesome Proteins Precede a Diagnosis of Breast Cancer Among Post-Menopausal Women
    Author Manuscript Published OnlineFirst on December 26, 2012; DOI: 10.1158/0008-5472.CAN-12-2560 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Autoantibody signatures involving glycolysis and splicesome proteins precede a diagnosis of breast cancer among post-menopausal women Jon J Ladd1, Timothy Chao1, Melissa M Johnson1, Ji Qiu1, Alice Chin1, Rebecca Israel1, Sharon J Pitteri1, Jianning Mao2, Mei Wu2, Lynn M Amon1, Martin McIntosh1, Christopher Li1, Ross Prentice1, Nora Disis2, Samir Hanash1,# 1 Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington, 98109, USA 2 Tumor Vaccine Group, University of Washington, 815 Mercer Street, 2nd Floor, Seattle, Washington, 98109, USA # Corresponding author: Samir Hanash, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, Phone: 206-667-5703, Fax: 206-667-2537, email: [email protected] Running title: Pre-diagnostic breast cancer autoantibody signatures Keywords: Breast cancer, Autoantibody, Glycolysis, Spliceosome, Pre-diagnostic Conflicts of interest: Dr. Disis has an ownership interest with University of Washington and consultant positions with VentiRX, Roche, BMS, EMD Serono and Immunovaccine. Word count: 3868 ; Figures/Tables: 4 Figures / 3 Tables Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 26, 2012; DOI: 10.1158/0008-5472.CAN-12-2560 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT We assessed the autoantibody repertoire of a mouse model engineered to develop breast cancer and the repertoire of autoantibodies in plasmas collected at a pre-clinical time point and at the time of clinical diagnosis of breast cancer.
    [Show full text]