Roles of RNA-Binding Proteins in DNA Damage Response
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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. -
High-Throughput Discovery of Novel Developmental Phenotypes
High-throughput discovery of novel developmental phenotypes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Dickinson, M. E., A. M. Flenniken, X. Ji, L. Teboul, M. D. Wong, J. K. White, T. F. Meehan, et al. 2016. “High-throughput discovery of novel developmental phenotypes.” Nature 537 (7621): 508-514. doi:10.1038/nature19356. http://dx.doi.org/10.1038/nature19356. Published Version doi:10.1038/nature19356 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071918 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nature. Manuscript Author Author manuscript; Manuscript Author available in PMC 2017 March 14. Published in final edited form as: Nature. 2016 September 22; 537(7621): 508–514. doi:10.1038/nature19356. High-throughput discovery of novel developmental phenotypes A full list of authors and affiliations appears at the end of the article. Abstract Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms #Corresponding author: [email protected]. -
RBMX Is a Novel Hepatic Transcriptional Regulator of SREBP-1C Gene Response to High-Fructose Diet
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 581 (2007) 218–222 RBMX is a novel hepatic transcriptional regulator of SREBP-1c gene response to high-fructose diet Tadashi Takemotoa, Yoshihiko Nishiob,*, Osamu Sekineb, Chikako Ikeuchib, Yoshio Nagaib, Yasuhiro Maenob, Hiroshi Maegawab, Hiroshi Kimuraa, Atsunori Kashiwagib a Division of Molecular Genetics in Medicine, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Shiga 520-2192, Japan b Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan Received 24 October 2006; accepted 1 December 2006 Available online 14 December 2006 Edited by Berend Wieringa nisms by which the high-fructose diet induces SREBP-1c gene Abstract In rodents a high-fructose diet induces metabolic derangements similar to those in metabolic syndrome. Previously expression in the liver. we suggested that in mouse liver an unidentified nuclear protein We previously reported a variation of susceptibility to these binding to the sterol regulatory element (SRE)-binding protein- metabolic disorders after monitoring the effects of high-fruc- 1c (SREBP-1c) promoter region plays a key role for the re- tose diet in different mouse strains [6]. Ten strains of inbred sponse to high-fructose diet. Here, using MALDI-TOF MASS mice were separated into CBA and DBA groups according technique, we identified an X-chromosome-linked RNA binding to their response to high-fructose diet. The hepatic mRNA motif protein (RBMX) as a new candidate molecule. In electro- expression of SREBP-1c in CBA/JN mice was remarkably ele- phoretic mobility shift assay, anti-RBMX antibody displaced the vated by high-fructose diet but not in DBA/2N. -
The Role of Arginine Methylation of Hnrnpul1 in the DNA Damage Response Pathway Gayathri Gurunathan
The role of arginine methylation of hnRNPUL1 in the DNA damage response pathway Gayathri Gurunathan Faculty of Medicine Division of Experimental Medicine McGill University, Montreal, Quebec, Canada August 2014 A Thesis Submitted to McGill University in Partial Fulfillment of the Requirements for the Degree of Master of Science © Gayathri Gurunathan 2014 Abstract Post-translational modifications play a key role in mediating the DNA damage response (DDR). It is well-known that serine/threonine phosphorylation is a major post-translational modification required for the amplification of the DDR; however, less is known about the role of other modifications, such as arginine methylation. It is known that arginine methylation of the DDR protein, MRE11, by protein arginine methyltransferase 1 (PRMT1) is essential for the response, as the absence of methylation of MRE11 in mice leads to hypersensitivity to DNA damage agents. Herein, we identify hnRNPUL1 as a substrate of PRMT1 and the methylation of hnRNPUL1 is required for DNA damage signalling. I show that several RGG/RG sequences of hnRNPUL1 are methylated in vitro by PRMT1. Recombinant glutathione S-transferase (GST) proteins harboring hnRNPUL1 RGRGRG, RGGRGG and a single RGG were efficient in vitro substrates of PRMT1. Moreover, I performed mass spectrometry analysis of Flag-hnRNPUL1 and identified the same sites methylated in vivo. PRMT1-depletion using RNA interference led to the hypomethylation of hnRNPUL1, consistent with PRMT1 being the only enzyme in vivo to methylate these sequences. We replaced the arginines with lysine in hnRNPUL1 (Flag- hnRNPUL1RK) such that this mutant protein cannot be methylated by PRMT1. Indeed Flag- hnRNPUL1RK was undetected using specific dimethylarginine antibodies. -
Genetic and Pharmacological Approaches to Preventing Neurodegeneration
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Genetic and Pharmacological Approaches to Preventing Neurodegeneration Marco Boccitto University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Neuroscience and Neurobiology Commons Recommended Citation Boccitto, Marco, "Genetic and Pharmacological Approaches to Preventing Neurodegeneration" (2012). Publicly Accessible Penn Dissertations. 494. https://repository.upenn.edu/edissertations/494 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/494 For more information, please contact [email protected]. Genetic and Pharmacological Approaches to Preventing Neurodegeneration Abstract The Insulin/Insulin-like Growth Factor 1 Signaling (IIS) pathway was first identified as a major modifier of aging in C.elegans. It has since become clear that the ability of this pathway to modify aging is phylogenetically conserved. Aging is a major risk factor for a variety of neurodegenerative diseases including the motor neuron disease, Amyotrophic Lateral Sclerosis (ALS). This raises the possibility that the IIS pathway might have therapeutic potential to modify the disease progression of ALS. In a C. elegans model of ALS we found that decreased IIS had a beneficial effect on ALS pathology in this model. This beneficial effect was dependent on activation of the transcription factor daf-16. To further validate IIS as a potential therapeutic target for treatment of ALS, manipulations of IIS in mammalian cells were investigated for neuroprotective activity. Genetic manipulations that increase the activity of the mammalian ortholog of daf-16, FOXO3, were found to be neuroprotective in a series of in vitro models of ALS toxicity. -
ATP Is Required for Interactions Between UAP56 and Two Conserved Mrna Export Proteins, Aly and CIP29, to Assemble the TREX Complex
ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex Kobina Dufu,1 Michaela J. Livingstone,2 Jan Seebacher,1 Steven P. Gygi,1 Stuart A. Wilson,2 and Robin Reed1,3 1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA; 2Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom The conserved TREX mRNA export complex is known to contain UAP56, Aly, Tex1, and the THO complex. Here, we carried out proteomic analysis of immunopurified human TREX complex and identified the protein CIP29 as the only new component with a clear yeast relative (known as Tho1). Tho1 is known to function in mRNA export, and we provide evidence that CIP29 likewise functions in this process. Like the known TREX components, a portion of CIP29 localizes in nuclear speckle domains, and its efficient recruitment to mRNA is both splicing- and cap-dependent. We show that UAP56 mediates an ATP-dependent interaction between the THO complex and both CIP29 and Aly, indicating that TREX assembly is ATP-dependent. Using recombinant proteins expressed in Escherichia coli, we show that UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex, and UAP56 bridges the interaction between CIP29 and Aly. We conclude that the interaction of two conserved export proteins, CIP29 and Aly, with UAP56 is strictly regulated by ATP during assembly of the TREX complex. [Keywords: CIP29; Aly; UAP56; TREX complex; Tho1; helicase] Supplemental material is available at http://www.genesdev.org. Received December 20, 2009; revised version accepted July 30, 2010. -
An Ancient Germ Cell-Specific RNA-Binding Protein Protects
RESEARCH ARTICLE An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning Ingrid Ehrmann1, James H Crichton2, Matthew R Gazzara3,4, Katherine James5, Yilei Liu1,6, Sushma Nagaraja Grellscheid1,7, TomazˇCurk8, Dirk de Rooij9,10, Jannetta S Steyn11, Simon Cockell11, Ian R Adams2, Yoseph Barash3,12*, David J Elliott1* 1Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom; 2MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; 3Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 4Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States; 5Life Sciences, Natural History Museum, London, United Kingdom; 6Department of Plant and Microbial Biology, University of Zu¨ rich, Zu¨ rich, Switzerland; 7School of Biological and Biomedical Sciences, University of Durham, Durham, United Kingdom; 8Laboratory of Bioinformatics, Faculty of Computer and Information Sciences, University of Ljubljana, Ljubljana, Slovenia; 9Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands; 10Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 11Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom; 12Department of Computer and Information Science, University of Pennsylvania, Philadelphia, United States *For correspondence: [email protected] (YB); [email protected] (DJE) Competing interests: The Abstract Male germ cells of all placental mammals express an ancient nuclear RNA binding authors declare that no protein of unknown function called RBMXL2. Here we find that deletion of the retrogene encoding competing interests exist. -
HNRPUL1 (HNRNPUL1) Rabbit Polyclonal Antibody Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TA345996 HNRPUL1 (HNRNPUL1) Rabbit Polyclonal Antibody Product data: Product Type: Primary Antibodies Applications: IF, IHC, IP, WB Recommended Dilution: IF, IP, WB, IHC Reactivity: Human Host: Rabbit Isotype: IgG Clonality: Polyclonal Immunogen: The immunogen for anti-HNRPUL1 antibody: synthetic peptide directed towards the C terminal of human HNRPUL1. Synthetic peptide located within the following region: TYPQPSYNQYQQYAQQWNQYYQNQGQWPPYYGNYDYGSYSGNTQGGTSTQ Formulation: Liquid. Purified antibody supplied in 1x PBS buffer with 0.09% (w/v) sodium azide and 2% sucrose. Note that this product is shipped as lyophilized powder to China customers. Purification: Protein A purified Conjugation: Unconjugated Storage: Store at -20°C as received. Stability: Stable for 12 months from date of receipt. Predicted Protein Size: 83 kDa Gene Name: heterogeneous nuclear ribonucleoprotein U like 1 Database Link: NP_653333 Entrez Gene 11100 Human Q9BUJ2 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 4 HNRPUL1 (HNRNPUL1) Rabbit Polyclonal Antibody – TA345996 Background: HNRPUL1 is a nuclear RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. This protein binds specifically to adenovirus E1B-55kDa oncoprotein. It may play an important role in nucleocytoplasmic RNA transport, and its function is modulated by E1B-55kDa in adenovirus-infected cells.This gene encodes a nuclear RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. -
The X-Chromosome RBMX Gene Is Expressed in Mammary Carcinoma
CANCER GENOMICS & PROTEOMICS 1: 39-44 (2004) The X-chromosome RBMX Gene is Expressed in Mammary Carcinoma F. GÓMEZ-ESQUERl, D. AGUDOl , F. MARTÍNEZ-ARRIBAS2, M.J. NUNEZ-VILLAR2, M. POLLÁN3 and J. SCHNEIDERl ,2 lUniversidad Rey Juan Carlos, Facultad de Ciencias de la Salud, Madrid; 2Fundación Tejerina-Centro de Patología de la Mama, Madrid; 3Centro Nacional de Epidemiologta, Madrid, Spain Abstract. Background: A gene located on the qll.23 regíon of conserved gender-specific genes, such as the ones regulating the the male chromosome, RBMY, which plays a role in male phenotype and spermatogenesis (3). The X chromosome, spermatogenesis, is down-regulated in testicular cancer. RBMY is in its turn, undergoes a specific phenomenon in females, known a diverged X-Y shared gene. The corresponding X chromosome as "X--chromosome inactivation", by which one of both alleles is gene, RBMX, is located on Xq26. Materials and Methods: We switched off at a very early stage of the embryonic development, studied fresh tissues from 122 infiltrating breast cancel':>' (99 ductal in order to avoid a double expression of genes if compared to infiltrating, 1910bular infiltrating and 4 tubular carcinomas) for their male counterparts. Sinee the inactivation of one or the the expression ofRBMXby means ofdífferential RT-PCR (reverse other allele occurs in a random fashion, adult females in the transcription-polymerase chain reaction), using beta-actin as an end are a mosaie of cells with either X allele inactivated (4). internal control and normalization standard, The obtained results The outcome of this regulatory proeess is that most genes of were compared with all available clinical and molecular data of the X chromosome are transcriptionally silenced, although the studied tumors (estrogen and progesterone receptors (ER & alterations do occur and are generally associated with grave PR), c-erb-B2, p53, Ki67, DNA-ploidy, Bcl-2, VEGF, CD105 disorders,like the Wiskott-Aldrich, the Leseh-Nyhan or the (endoglin), histologic variety, histologic and nuclear grade and Barth syndromes. -
HNRPUL1 (HNRNPUL1) (NM 007040) Human Tagged ORF Clone Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for RC200576L3 HNRPUL1 (HNRNPUL1) (NM_007040) Human Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: HNRPUL1 (HNRNPUL1) (NM_007040) Human Tagged ORF Clone Tag: Myc-DDK Symbol: HNRNPUL1 Synonyms: E1B-AP5; E1BAP5; HNRPUL1 Vector: pLenti-C-Myc-DDK-P2A-Puro (PS100092) E. coli Selection: Chloramphenicol (34 ug/mL) Cell Selection: Puromycin ORF Nucleotide The ORF insert of this clone is exactly the same as(RC200576). Sequence: Restriction Sites: SgfI-MluI Cloning Scheme: ACCN: NM_007040 ORF Size: 2568 bp This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 HNRPUL1 (HNRNPUL1) (NM_007040) Human Tagged ORF Clone – RC200576L3 OTI Disclaimer: The molecular sequence of this clone aligns with the gene accession number as a point of reference only. However, individual transcript sequences of the same gene can differ through naturally occurring variations (e.g. polymorphisms), each with its own valid existence. This clone is substantially in agreement with the reference, but a complete review of all prevailing variants is recommended prior to use. More info OTI Annotation: This clone was engineered to express the complete ORF with an expression tag. Expression varies depending on the nature of the gene. RefSeq: NM_007040.2 RefSeq Size: 3892 bp RefSeq ORF: 2571 bp Locus ID: 11100 UniProt ID: Q9BUJ2 Domains: SAP, SPRY Protein Families: Druggable Genome MW: 95.8 kDa Gene Summary: This gene encodes a nuclear RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. -
RBMX Family Proteins Connect the Fields of Nuclear RNA Processing
International Journal of Biochemistry and Cell Biology 108 (2019) 1–6 Contents lists available at ScienceDirect International Journal of Biochemistry and Cell Biology journal homepage: www.elsevier.com/locate/biocel RBMX family proteins connect the fields of nuclear RNA processing, disease and sex chromosome biology T ⁎ David J. Elliott , Caroline Dalgliesh, Gerald Hysenaj, Ingrid Ehrmann Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK ARTICLE INFO ABSTRACT Keywords: RBMX is a ubiquitously expressed nuclear RNA binding protein that is encoded by a gene on the X chromosome. RNA splicing RBMX belongs to a small protein family with additional members encoded by paralogs on the mammalian Y Gene expression chromosome and other chromosomes. These RNA binding proteins are important for normal development, and Brain development also implicated in cancer and viral infection. At the molecular level RBMX family proteins contribute to splicing Testis control, transcription and genome integrity. Establishing what endogenous genes and pathways are controlled by Cancer RBMX and its paralogs will have important implications for understanding chromosome biology, DNA repair and mammalian development. Here we review what is known about this family of RNA binding proteins, and identify important current questions about their functions. 1. Introduction et al., 1993). While RBMX is expressed ubiquitously through the body, RBMY genes are specifically expressed in germ cells (cells that even- RBMX (an acronym of RNA Binding Motif protein, X-linked) was tually develop into sperm). Multiple RBMY genes are present on the originally identified as one of a functionally diverse group of nuclear long arm of the human Y chromosome, each encoding 496 amino acid proteins that bind to polyadenylated RNA. -
DNA Damage Triggers SAF-A and RNA Biogenesis
Published online 16 July 2014 Nucleic Acids Research, 2014, Vol. 42, No. 14 9047–9062 doi: 10.1093/nar/gku601 DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal Sebastien´ Britton1,2,3,†, Emma Dernoncourt1,2,3,†, Christine Delteil1,2,3, Carine Froment1,2, Odile Schiltz1,2, Bernard Salles1,2, Philippe Frit1,2,3,* and Patrick Calsou1,2,3,* 1CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), BP 64182, 205 route de Narbonne, F-31077 Toulouse, Cedex 4, France, 2Universite´ de Toulouse, UPS, IPBS, F-31077 Toulouse, France and 3Equipe Labellisee´ Ligue Nationale Contre le Cancer Received March 11, 2014; Revised June 01, 2014; Accepted June 23, 2014 ABSTRACT INTRODUCTION We previously identified the heterogeneous ribonu- Deoxyribonucleic acid (DNA) double-strand break (DSB) cleoprotein SAF-A/hnRNP U as a substrate for DNA- is the most toxic type of DNA damage. If improperly re- PK, a protein kinase involved in DNA damage re- paired, DSBs can cause cell death or mutations and gross sponse (DDR). Using laser micro-irradiation in hu- chromosomal rearrangements promoting cancer develop- man cells, we report here that SAF-A exhibits a two- ment (1–4). In mammalian cells, DSBs initiate a global DNA damage response (DDR) to overcome their toxicity phase dynamics at sites of DNA damage, with a and maintain genome stability. DDR includes lesions detec- rapid and transient recruitment followed by a pro- tion, checkpoint activation, modulation of gene expression longed exclusion. SAF-A recruitment corresponds to and DNA repair (5–9). DDR defects manifest as a variety its binding to Poly(ADP-ribose) while its exclusion of human diseases, including neurodegenerative disorders, is dependent on the activity of ATM, ATR and DNA- immunodeficiency, infertility and cancer (5).