DOCSLIB.ORG

BEE : a Web Service for Biomedical Entity Exploration

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
BEE : a Web Service for Biomedical Entity Exploration bioRxiv preprint doi: https://doi.org/10.1101/2020.01.03.893594; this version posted January 3, 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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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. BEE : a web service for biomedical entity exploration Jin-uk Jung1,, Jin-Muk Lim1,, Hyunwhan Joe1,, and Hong-Gee Kim1, 1410, Dentisty Graduate School of Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea Recently there has been a trend in bioinformatics to produce on intuitiveness and simplicity. BEE’s straightforward inter- and manage large quantities of data to better explain complex face minimizes the level of questions and input parameters, life phenomena through relationship and interactions among reducing the difficulty for new users. In addition, the sys- biomedical entities. This increase in data leads to a need for tem can be easily expanded by minimizing the difficulty of more efficient management and searching capabilities. As a re- adding and modifying a new biomedical entity with a simple sult, Semantic Web technologies have been applied to biomedi- data structure. cal data. To use these technologies, users have to learn a query language such as SPARQL in order to ask complex queries such as ‘What are the drugs associated with the disease breast carci- MATERIALS AND METHODS : Inside of noma and Osteoporosis but not the gene ESR1’. BEE was devel- BEE oped to overcome the limitations and difficulties of learning such query languages. Our proposed system provides an intuitive A. Design principle. The development focus was to mini- and effective query interface based on natural language. Our mize the difficulty of query generation for users, which was system is a heterogeneous biomedical entity query system based the limitation of existing search systems. Therefore, devel- on pathway, drug, microRNA, disease and gene datasets from opment proceeded by setting up the interface to be as simple DGIdb, Tarbase, Human Phenotype Ontology and Reactome , and intuitive as possible. Gene Ontology, KEGG gene set of MSigDB. User queries can be joined with union, intersection and negation operators. The Subsequent considerations were focused on minimizing the system also allows for selected results to be saved and later com- query step and reducing the required parameters. Also, for in- bined with newly created queries. To the best of our knowledge, tuitive use, the parameter input follows the order of words in BEE is the first system that supports condition search based on natural language. This minimizes the learning curve of how the relationship of heterogeneous biomedical entities and is ex- to use the system and allows the user to use the application pected to be used in various fields of bioinformatics such as in immediately without any difficulties. The system provides drug repositioning candidate selection as well as simple knowl- features that save/load the search history, and supports ex- edge search. porting search results into various formats such as clipboard, Correspondence: [email protected] CSV, and Excel. In addition, BEE has a flexible schema that allows developers to add existing and new biomedical entity types, while ensuring that there is no impact of change to the Introduction existing system. In the last decades, bioinformaticians have been trying to dis- cover the relationships between genes and other biomedical B. Design principle. There are five entity types used in entities. As a result, the amount of data on gene associationsDRAFTBEE: gene, disease, drug, pathway and microRNA. Drug- with biomedical entities such as diseases, drugs and pathways gene interaction data were extracted from DGIdb(1). DGIdb have exploded. Consequently, this growth in data has lead to is a dataset that integrates human genes and drug-related an increasing need for an efficient search tool for the relation- data related to diseases based on 13 major sources. It pro- ship between more complex biomedical entities. vides more than 14,000 drug-gene interaction data between BEE is a web service that was developed for the needs of more than 2,600 genes and 6,300 drugs. It was last up- these users. The system is an entity search system that can dated on 2018-01-25. The gene symbol, Entrez ID, drug answer simple questions such as ’what are the pathways con- name and ChEmBL ID included in the schema were extracted taining gene A and gene B’, to more complex questions such and loaded into the BEE database. Second, disease-gene as- as ’what are the drugs associated with disease s1 and s2 with- sociation is based on data provided by the Human Pheno- out gene g1 targeted drugs’, which requires knowledge be- type Ontology(HPO)(2). HPO provides a standard vocabu- tween heterologous biomedical entities. Our primary goal lary of phenotypic features of human genetic or other dis- is to develop an easy-to-create query system that can get re- eases. HPO data is updated once a month, and the prepro- sults for complex queries. To search with multi-queries in cessing module in our system extracts the entrez id, gene existing systems, the user needs to learn a query language symbol, HPO term, and HPO term ID data from the files such as SPARQL or adapt to the use of the complex inter- provided by HPO and stores them in our database. Third, face provided by the system. It results in a deterioration of microRNA data is based on TarBase(3). TarBase provides user accessibility. The design principle of BEE is focused sequence data, target gene information and annotations on Jin-uk Jung et al. | bioRχiv | January 3, 2020 | 1–4 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.03.893594; this version posted January 3, 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. a web service, and integrates information on cell-type spe- bles (https://datatables.net/). cific miRNA-gene regulation information. Our preprocessing module extracted the gene symbol and miRNA information from the data provided by the source, and filtered it by the species Homo sapiens. TarBase was last updated on 2018- 3-12. Fourth, the pathway-gene association data was col- lected from the Gene Ontology(Biological process)(2)(4), Reactome(5), and KEGG(6) Gene set data is provided by the Molecular Signatures Database(MSigDB)(7). MSigDB pro- vides only gene information for each pathway and removes the context. Our system imported data which was released in MSigDB 7.0. Finally, gene data was composed by integrating Fig. 1. Entity association in BEE all gene symbols linked to the above disease, drug, pathway, and microRNA. The BEE database consists of 25,033 genes, Results 20,370 diseases, 5256 pathways, 12785 drugs, and 1034 mi- croRNAs. E. BEE web server. The system is based on the gene, drug, disease, pathway, and microRNA database loaded by the pre- C. System model. A Model of BEE B = (G,E,RE−G). processing module, and the loaded data continues to grow as G is a set of gene {g1,...,gv}. E is a set of entity types the data sources in each silo update. {D,S,P,M}. It includes a set of drugs D{d1,...,dw}, a On the first screen of BEE, the user can enter a query. As set of diseases S{s1,...,sx}, a set of pathways P {p1,...,py}, a result, the system provides network visualization informa- and a set of microRNAs M{m1,...,mz}. And RE−G is a tion and query results between entities according to the input set of relations between ei ∈ E and gi ∈ G that is RE−G ⊆ query, and the query result can be saved and used as part of E × G. For example, as shown in Figure 1, given dw ∈ D the query chain. and gv ∈ G, (dw,gv) ∈ Rdw−gv means "drug dw target to gene gv". i.e. RD−G = {(g1,d1),(g1,d2)}, RS−G = F. Query interface. The system provides an interface for {(g1,s1),(g2,s2),(g3,s2),(g4,s2)}. getting answers by combining two or more query sets and And also, the system model has three functions, their operators. There are three elements that make up a query gen,rgen,ext. First, gen, given an entity ei ∈ E, set: Answer entity type, Question entity type and Question gen(ei) = {g ∈ G|(e,g) ∈ Rei−G}. The function takes an entity name. As shown in Table 1, in query set 1, for the element of entity as parameter, returns the gene set associated question "What are the drugs associated with Breast carci- with the input entity. E.g. gen({s1}) = {g1,g2}. Second, noma", the Answer entity type is ’Drug’. ’Disease’ is the given a gene gi ∈ G, rgen(gi) = {{e} ⊆ |(e,g) ∈ RE−G}. question entity type and ’Breast carcinoma’ is the Question The function rgen takes an element of gene entity as a pa- entity name. There are also three query operators which are rameter and returns all entities associated with the input gene. union, intersection and negation. For example, the question E.g. rgen({g1}) = {d1,d2,s1}, rgen({g2}) = {s1,s2}. ’What are the drugs associated with disease Breast carcinoma Third, the ext function extracts and returns a specific type and Osteoporosis but not gene ESR1’ can be obtained by set- of entity from the set of input entities.
Load more

Recommended publications
  • Phosphatidylinositol-3-Kinase Related Kinases (Pikks) in Radiation-Induced Dna Damage
    Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2012, vol. 81(4), p. 177-187 ISSN 0372-7025 DOI: 10.31482/mmsl.2012.025 REVIEW ARTICLE PHOSPHATIDYLINOSITOL-3-KINASE RELATED KINASES (PIKKS) IN RADIATION-INDUCED DNA DAMAGE Ales Tichy 1, Kamila Durisova 1, Eva Novotna 1, Lenka Zarybnicka 1, Jirina Vavrova 1, Jaroslav Pejchal 2, Zuzana Sinkorova 1 1 Department of Radiobiology, Faculty of Health Sciences in Hradec Králové, University of Defence in Brno, Czech Republic 2 Centrum of Advanced Studies, Faculty of Health Sciences in Hradec Králové, University of Defence in Brno, Czech Republic. Received 5 th September 2012. Revised 27 th November 2012. Published 7 th December 2012. Summary This review describes a drug target for cancer therapy, family of phosphatidylinositol-3 kinase related kinases (PIKKs), and it gives a comprehensive review of recent information. Besides general information about phosphatidylinositol-3 kinase superfamily, it characterizes a DNA-damage response pathway since it is monitored by PIKKs. Key words: PIKKs; ATM; ATR; DNA-PK; Ionising radiation; DNA-repair ABBREVIATIONS therapy and radiation play a pivotal role. Since cancer is one of the leading causes of death worldwide, it is DSB - double stand breaks, reasonable to invest time and resources in the enligh - IR - ionising radiation, tening of mechanisms, which underlie radio-resis - p53 - TP53 tumour suppressors, tance. PI - phosphatidylinositol. The aim of this review is to describe the family INTRODUCTION of phosphatidyinositol 3-kinases (PI3K) and its func - tional subgroup - phosphatidylinositol-3-kinase rela - An efficient cancer treatment means to restore ted kinases (PIKKs) and their relation to repairing of controlled tissue growth via interfering with cell sig - radiation-induced DNA damage.
    [Show full text]
  • Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren
    biomolecules Article Generation of a Mouse Model Lacking the Non-Homologous End-Joining Factor Mri/Cyren 1,2, 1,2, 1,2, 1,2 Sergio Castañeda-Zegarra y , Camilla Huse y, Øystein Røsand y, Antonio Sarno , Mengtan Xing 1,2, Raquel Gago-Fuentes 1,2, Qindong Zhang 1,2, Amin Alirezaylavasani 1,2, Julia Werner 1,2,3, Ping Ji 1, Nina-Beate Liabakk 1, Wei Wang 1, Magnar Bjørås 1,2 and Valentyn Oksenych 1,2,4,* 1 Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, 7491 Trondheim, Norway; [email protected] (S.C.-Z.); [email protected] (C.H.); [email protected] (Ø.R.); [email protected] (A.S.); [email protected] (M.X.); [email protected] (R.G.-F.); [email protected] (Q.Z.); [email protected] (A.A.); [email protected] (J.W.); [email protected] (P.J.); [email protected] (N.-B.L.); [email protected] (W.W.); [email protected] (M.B.) 2 St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Postboks 3250, Sluppen, 7006 Trondheim, Norway 3 Molecular Biotechnology MS programme, Heidelberg University, 69120 Heidelberg, Germany 4 Department of Biosciences and Nutrition (BioNut), Karolinska Institutet, 14183 Huddinge, Sweden * Correspondence: [email protected]; Tel.: +47-913-43-084 These authors contributed equally to this work. y Received: 7 November 2019; Accepted: 26 November 2019; Published: 28 November 2019 Abstract: Classical non-homologous end joining (NHEJ) is a molecular pathway that detects, processes, and ligates DNA double-strand breaks (DSBs) throughout the cell cycle.
    [Show full text]
  • A Process of Resection-Dependent Nonhomologous End Joining Involving the Goddess Artemis
    A process of resection-dependent nonhomologous end joining involving the goddess Artemis Article (Published Version) Jeggo, Penny and Löbrich, Markus (2017) A process of resection-dependent nonhomologous end joining involving the goddess Artemis. Trends in Biochemical Sciences, 42 (9). pp. 690-701. ISSN 0968-0004 This version is available from Sussex Research Online: http://sro.sussex.ac.uk/id/eprint/77876/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the URL above for details on accessing the published version. Copyright and reuse: Sussex Research Online is a digital repository of the research output of the University. Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available. Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. http://sro.sussex.ac.uk [160_TD$IF]Opinion A Process of Resection- Dependent Nonhomologous End Joining Involving the Goddess Artemis Markus Löbrich1,* and Penny Jeggo2,* DNA double-strand breaks (DSBs) are a hazardous form of damage that can Trends potentially cause cell death or genomic rearrangements.
    [Show full text]
  • Radiation-Sensitive Severe Combined Immunodeficiency (RS-SCID)
    Radiation-sensitive severe combined immunodeficiency (RS-SCID) Contact details Introduction Molecular Genetics Service Severe combined immunodeficiency (SCID) is a group of genetically and Level 6, York House phenotypically heterogeneous disorders that can be immunologically classified by the 37 Queen Square absence or presence of T, B, and natural killer (NK) cells. The most severe form of - - + London, WC1N 3BH SCID has the T B NK phenotype, accounting for ~20% of all cases in which patients T +44 (0) 20 7762 6888 present with a virtual absence of both circulating T and B cells, while maintaining a F +44 (0) 20 7813 8578 normal level and function of NK cells. This form of SCID is caused by autosomal recessive mutations in at least three primary genes necessary for V(D)J recombination, RAG1, RAG2, and DCLRE1C (ARTEMIS). DCLRE1C mutations Samples required cause a T and B cell deficient form of SCID that is clinically indistinguishable from a • 5ml venous blood in plastic EDTA RAG1/RAG2 disorder. Infants present with severe recurrent viral, bacterial or fungal bottles (>1ml from neonates) infections and failure-to-thrive. Defects in DCLRE1C can be distinguished from RAG • Prenatal testing must be arranged defects because the former has the additional feature of increased sensitivity to in advance, through a Clinical ionising radiation in bone marrow and fibroblast cells. Genetics department if possible. The DNA crosslink repair 1C gene (DCLRE1C; MIM 605988) encodes ARTEMIS • Amniotic fluid or CV samples which is an essential factor of V(D)J recombination during lymphocyte development should be sent to Cytogenetics for and in the repair of DNA double-strand breaks (DSB) by the non-homologous end dissecting and culturing, with joining (NHEJ) pathway.
    [Show full text]
  • DOE Systems Biology Knowledgebase Implementation Plan
    DOE Systems Biology Knowledgebase Implementation Plan As part of the U.S. Department of Energy’s (DOE) Office of Science, the Office of Biological and Environmental Research (BER) supports fundamental research and technology development aimed at achieving predictive, systems-level understand- ing of complex biological and environmental systems to advance DOE missions in energy, climate, and environment. DOE Contact Susan Gregurick 301.903.7672, [email protected] Office of Biological and Environmental Research U.S. Department of Energy Office of Science www.science.doe.gov/Program_Offices/BER.htm Acknowledgements The DOE Office of Biological and Environmental Research appreciates the vision and leadership exhibited by Bob Cottingham and Brian Davison (both from Oak Ridge National Laboratory) over the past year to conceptualize and guide the effort to create the DOE Systems Biology Knowledgebase Implementation Plan. Furthermore, we are grateful for the valuable contributions from about 300 members of the scientific community to organize, participate in, and provide the intellectual output of 5 work- shops, which culminated with the implementation plan. The plan was rendered into its current form by the efforts of the Biological and Environmental Research Information System (Oak Ridge National Laboratory). The report is available via • www.genomicscience.energy.gov/compbio/ • www.science.doe.gov/ober/BER_workshops.html • www.systemsbiologyknowledgebase.org Suggested citation for entire report: U.S. DOE. 2010. DOE Systems Biology Knowledgebase Implementation Plan. U.S. Department of Energy Office of Science (www.genomicscience.energy.gov/compbio/). DOE Systems Biology Knowledgebase Implementation Plan September 30, 2010 Office of Biological and Environmental Research The document is available via genomicscience.energy.gov/compbio/.
    [Show full text]
  • Diagnostic Interpretation of Genetic Studies in Patients with Primary
    AAAAI Work Group Report Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology Ivan K. Chinn, MD,a,b Alice Y. Chan, MD, PhD,c Karin Chen, MD,d Janet Chou, MD,e,f Morna J. Dorsey, MD, MMSc,c Joud Hajjar, MD, MS,a,b Artemio M. Jongco III, MPH, MD, PhD,g,h,i Michael D. Keller, MD,j Lisa J. Kobrynski, MD, MPH,k Attila Kumanovics, MD,l Monica G. Lawrence, MD,m Jennifer W. Leiding, MD,n,o,p Patricia L. Lugar, MD,q Jordan S. Orange, MD, PhD,r,s Kiran Patel, MD,k Craig D. Platt, MD, PhD,e,f Jennifer M. Puck, MD,c Nikita Raje, MD,t,u Neil Romberg, MD,v,w Maria A. Slack, MD,x,y Kathleen E. Sullivan, MD, PhD,v,w Teresa K. Tarrant, MD,z Troy R. Torgerson, MD, PhD,aa,bb and Jolan E. Walter, MD, PhDn,o,cc Houston, Tex; San Francisco, Calif; Salt Lake City, Utah; Boston, Mass; Great Neck and Rochester, NY; Washington, DC; Atlanta, Ga; Rochester, Minn; Charlottesville, Va; St Petersburg, Fla; Durham, NC; Kansas City, Mo; Philadelphia, Pa; and Seattle, Wash AAAAI Position Statements,Work Group Reports, and Systematic Reviews are not to be considered to reflect current AAAAI standards or policy after five years from the date of publication. The statement below is not to be construed as dictating an exclusive course of action nor is it intended to replace the medical judgment of healthcare professionals.
    [Show full text]
  • Artemis, a Novel DNA Double-Strand Break Repair/V(D)J Recombination Protein, Is Mutated in Human Severe Combined Immune Deficiency
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Cell, Vol. 105, 177±186, April 20, 2001, Copyright 2001 by Cell Press Artemis, a Novel DNA Double-Strand Break Repair/V(D)J Recombination Protein, Is Mutated in Human Severe Combined Immune Deficiency Despina Moshous,* Isabelle Callebaut,² is flanked by recombination signal sequences (RSSs) Re gina de Chasseval,* Barbara Corneo,* composed of conserved heptamers and nonamers sep- Marina Cavazzana-Calvo,* FrancË oise Le Deist,* arated by random sequences of either 12 or 23 nucleo- Ilhan Tezcan,³ Ozden Sanal,³ Yves Bertrand,§ tides. V(D)J recombination can be roughly divided into Noel Philippe,§ Alain Fischer,* three steps. First, the RAG1 and RAG2 proteins initiate and Jean-Pierre de Villartay* the rearrangement process through the recognition of *De veloppement Normal et Pathologique the RSS and the introduction of a DNA double-strand du SysteÁ me Immunitaire break (dsb) at the border of the heptamer (Schatz et INSERM U429 al., 1989; Oettinger et al., 1990). The subsequent step Hoà pital Necker Enfants Malades consists of recognition and signaling of the DNA damage 149 rue de SeÁ vres to the ubiquitously expressed DNA repair machinery. 75015 Paris The description of the murine scid anomaly, character- France ized by a lack of circulating mature B and T lymphocytes ² LMCP, CNRS UMR C7590 (Bosma et al., 1983), as a general DNA repair defect Universite s Paris 6 et Paris 7 accompanied by an increased sensitivity to ionizing ra- Paris 75005 diation or other agents causing DNA dsb, provided the France link between V(D)J recombination and DNA dsb repair ³ Immunology Division (Fulop and Phillips, 1990; Biedermann et al., 1991; Hen- Hacettepe University drickson et al., 1991).
    [Show full text]
  • Anti-Artemis (DCLRE1C) Produced in Rabbit, Affinity Isolated Antibody
    Anti-Artemis (DCLRE1C) Produced in rabbit, Affinity Isolated Antibody Product Number A 1605 Product Description Precautions and Disclaimer Anti-Artemis (DCLRE1C) is produced in rabbit using as Due to the sodium azide content a material safety sheet immunogen a peptide corresponding to the human (MSDS) for this product has been sent to the attention Artemis protein (amino acids 677-692). The antibody is of the safety officer of your institution. Consult the affinity-purified using the immunizing peptide MSDS for information regarding hazardous and safe immobilized on agarose. handling practices. Anti-Artemis (DCLRE1C) reacts with residues 677-692 Storage/Stability (GESIAKKRKCSLLDT) of human artemis. The antibody Store at -20 °C. The antibody may be stored at 2-8 °C may be used in immunoblotting (~78 kDa). A weak for up to three months. For prolonged storage, freeze in signal is often seen due to low expression levels. working aliquots at -20 °C. Avoid repeated freezing and thawing. Do not store in a “frost-free” freezer. Artemis is a novel protein that is involved in V(D)J recombination/DNA repair. Mutations cause human T- Product Profile B-severe combined immunodeficiency associated with For immunoblotting, a working antibody dilution of increased cellular radiosenstivity (RS-SCID). 1:250-1:1,000 is recommended using human testis lysate. Reagent The antibody is supplied as a solution of ~1 mg/mL in Note: In order to obtain the best results in various phosphate buffered saline containing 0.02% sodium techniques and preparations, we recommend deter- azide. mining optimal working dilutions by titration. References 1.
    [Show full text]
  • Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency
    UCSF UC San Francisco Previously Published Works Title Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency Permalink https://escholarship.org/uc/item/8h27g83n Journal HUMAN GENE THERAPY, 28(1) ISSN 1043-0342 Authors Punwani, Divya Kawahara, Misako Yu, Jason et al. Publication Date 2017 DOI 10.1089/hum.2016.064 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency Divya Punwani,1,{ Misako Kawahara,1,{ Jason Yu,1,{ Ukina Sanford,1 Sushmita Roy,1 Kiran Patel,1 Denise A. Carbonaro,2 Andrea D. Karlen,3 Sara Khan,1 Kenneth Cornetta,4 Michael Rothe,5 Axel Schambach,5 Donald B. Kohn,2 Harry L. Malech,6 R. Scott McIvor,3 Jennifer M. Puck,1,*,{ and Morton J. Cowan1,*,{ 1Department of Pediatrics, University of California School of Medicine and University of California San Francisco Benioff Children’s Hospital, San Francisco, San Francisco, California; 2Departments of Microbiology, Immunology and Molecular Genetics and Pediatrics, University of California Los Angeles, Los Angeles, California; 3Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota; 4Department of Medical and Molecular Genetics, Indiana University, and the Indiana University Viral Production Facility, Indianapolis, Indiana; 5Institute for Experimental Hematology, Hannover Medical School, Hannover, Germany; 6Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Division of Intramural Research, National Institutes of Health, Bethesda, Maryland. {These authors contributed equally to this study. During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double- strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining.
    [Show full text]
  • Severe Combined Immunodeficiency (SCID) Presenting in Childhood
    Clinical Immunology 200 (2019) 16–18 Contents lists available at ScienceDirect Clinical Immunology journal homepage: www.elsevier.com/locate/yclim Brief Communication Severe combined immunodeficiency (SCID) presenting in childhood, with T agammaglobulinemia, associated with novel compound heterozygous mutations in DCLRE1C ⁎ Mikael Sundina, Per Maritsb, Kim Rammea, Antonios G.A. Koliosc,d, Jakob Nilssonb,c,d, a The Pediatric Hematology, Immunology and HCT Section, Astrid Lindgren Children's Hospital, Stockholm, Sweden b Department of Clinical Immunology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden c Department of Clinical Immunology, University Hospital Zurich, Switzerland d Faculty of Medicine, University of Zurich, Zurich, Switzerland ARTICLE INFO ABSTRACT Keywords: Severe combined immunodeficiency (SCID) can be caused by deleterious mutations in DCLRE1C, leading to Severe combined immunodeficiency deficient non-homologous end joining by compromising the function of the Artemis protein. This impairsthe DCLRE1C process of V(D)J recombination of the T- and B-cell receptors and typically results in radiosensitive T−,B−, NK+ Artemis SCID presenting during the first months of life. We present a case of a 3-year-old girl with two novel compound Agammaglobulinemia heterozygous variants in DCLRE1C (c.58G > C and c.374A > C) that were associated with marked reduced numbers of peripheral T- and B-cells and undetectable total serum IgG. Despite the severe laboratory phenotype, the patient had a normal development, albeit failure to thrive (−2.5 to −3 SD), during her first years of life including day-care attendance at preschool for 1.5 years. After being diagnosed with pneumonia the clinical picture of SCID was recognized and the girl successfully underwent hematopoietic stem-cell transplantation.
    [Show full text]
  • A Process of Resection-Dependent Nonhomologous End
    [160_TD$IF]Opinion A Process of Resection- Dependent Nonhomologous End Joining Involving the Goddess Artemis Markus Löbrich1,* and Penny Jeggo2,* DNA double-strand breaks (DSBs) are a hazardous form of damage that can Trends potentially cause cell death or genomic rearrangements. In mammalian G1- and A c-NHEJ pathway has been defined G2-phase cells, DSBs are repaired with two-component kinetics. In both involving resection of DSB ends prior phases, a fast process uses canonical nonhomologous end joining (c-NHEJ) to their ligation in G1. Thus, the two to repair the majority of DSBs. In G2, slow repair occurs by homologous main pathways for repairing DSBs in G1 human cells are resection-inde- recombination. The slow repair process in G1 also involves c-NHEJ proteins pendent and resection-dependent c- but additionally requires the nuclease Artemis and DNA end resection. Here, we NHEJ. consider the nature of slow DSB repair in G1 and evaluate factors determining The resection process in G1 uses whether DSBs are repaired with fast or slow kinetics. We consider limitations in many of the same factors used for our current knowledge and present a speculative model for Artemis-dependent resection during homologous recom- bination in G2 but orchestrates them in c-NHEJ and the environment underlying its usage. a manner suited to a c-NHEJ process. Since Artemis is the only identified fac- tor involved in the resection process DNA DSBs Are Repaired by Multiple Pathways whose loss leads to unrepaired DSBs, The ability to repair DNA DSBs is a critical determinant of survival to ionising radiation (IR) and we refer to this process as Artemis- other DSB-inducing agents.
    [Show full text]
  • Consensus Phosphorylation Sites Lacking Phosphatidylinositol 3-Like
    Repair of Chromosomal RAG-Mediated DNA Breaks by Mutant RAG Proteins Lacking Phosphatidylinositol 3-Like Kinase Consensus Phosphorylation Sites This information is current as of October 2, 2021. Eric J. Gapud, Baeck-Seung Lee, Grace K. Mahowald, Craig H. Bassing and Barry P. Sleckman J Immunol 2011; 187:1826-1834; Prepublished online 8 July 2011; doi: 10.4049/jimmunol.1101388 Downloaded from http://www.jimmunol.org/content/187/4/1826 Supplementary http://www.jimmunol.org/content/suppl/2011/07/08/jimmunol.110138 Material 8.DC1 http://www.jimmunol.org/ References This article cites 51 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/187/4/1826.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 2, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Repair of Chromosomal RAG-Mediated DNA Breaks by Mutant RAG Proteins Lacking Phosphatidylinositol 3-Like Kinase Consensus Phosphorylation Sites Eric J.
    [Show full text]