Activation-Induced Cytidine Deaminase Hypermutation in The
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Evolutionary Origins of DNA Repair Pathways: Role of Oxygen Catastrophe in the Emergence of DNA Glycosylases
cells Review Evolutionary Origins of DNA Repair Pathways: Role of Oxygen Catastrophe in the Emergence of DNA Glycosylases Paulina Prorok 1 , Inga R. Grin 2,3, Bakhyt T. Matkarimov 4, Alexander A. Ishchenko 5 , Jacques Laval 5, Dmitry O. Zharkov 2,3,* and Murat Saparbaev 5,* 1 Department of Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany; [email protected] 2 SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Ave., 630090 Novosibirsk, Russia; [email protected] 3 Center for Advanced Biomedical Research, Department of Natural Sciences, Novosibirsk State University, 2 Pirogova St., 630090 Novosibirsk, Russia 4 National Laboratory Astana, Nazarbayev University, Nur-Sultan 010000, Kazakhstan; [email protected] 5 Groupe «Mechanisms of DNA Repair and Carcinogenesis», Equipe Labellisée LIGUE 2016, CNRS UMR9019, Université Paris-Saclay, Gustave Roussy Cancer Campus, F-94805 Villejuif, France; [email protected] (A.A.I.); [email protected] (J.L.) * Correspondence: [email protected] (D.O.Z.); [email protected] (M.S.); Tel.: +7-(383)-3635187 (D.O.Z.); +33-(1)-42115404 (M.S.) Abstract: It was proposed that the last universal common ancestor (LUCA) evolved under high temperatures in an oxygen-free environment, similar to those found in deep-sea vents and on volcanic slopes. Therefore, spontaneous DNA decay, such as base loss and cytosine deamination, was the Citation: Prorok, P.; Grin, I.R.; major factor affecting LUCA’s genome integrity. Cosmic radiation due to Earth’s weak magnetic field Matkarimov, B.T.; Ishchenko, A.A.; and alkylating metabolic radicals added to these threats. -
Case of the Anti HIV-1 Antibody, B12
Spectrum of Somatic Hypermutations and Implication on Antibody Function: Case of the anti HIV-1 antibody, b12 Mesfin Mulugeta Gewe A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2015 Reading Committee: Roland Strong, Chair Nancy Maizels Jessica A. Hamerman Program Authorized to Offer Degree: Molecular and Cellular Biology i ii ©Copyright 2015 Mesfin Mulugeta Gewe iii University of Washington Abstract Spectrum of Somatic Hypermutations and Implication on Antibody Function: Case of the anti HIV-1 antibody, b12 Mesfin Mulugeta Gewe Chair of the Supervisory Committee: Roland Strong, Full Member Fred Hutchinson Cancer Research Center Sequence diversity, ability to evade immune detection and establishment of human immunodeficiency virus type 1 (HIV-1) latent reservoirs present a formidable challenge to the development of an HIV-1 vaccine. Structure based vaccine design stenciled on infection elicited broadly neutralizing antibodies (bNAbs) is a promising approach, in some measure to circumvent existing challenges. Understanding the antibody maturation process and importance of the high frequency mutations observed in anti-HIV-1 broadly neutralizing antibodies are imperative to the success of structure based vaccine immunogen design. Here we report a biochemical and structural characterization for the affinity maturation of infection elicited neutralizing antibodies IgG1 b12 (b12). We investigated the importance of affinity maturation and mutations accumulated therein in overall antibody function and their potential implications to vaccine development. Using a panel of point iv reversions, we examined relevance of individual amino acid mutations acquired during the affinity maturation process to deduce the role of somatic hypermutation in antibody function. -
The Regulation of Carbamoyl Phosphate Synthetase-Aspartate Transcarbamoylase-Dihydroorotase (Cad) by Phosphorylation and Protein-Protein Interactions
THE REGULATION OF CARBAMOYL PHOSPHATE SYNTHETASE-ASPARTATE TRANSCARBAMOYLASE-DIHYDROOROTASE (CAD) BY PHOSPHORYLATION AND PROTEIN-PROTEIN INTERACTIONS Eric M. Wauson A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology. Chapel Hill 2007 Approved by: Lee M. Graves, Ph.D. T. Kendall Harden, Ph.D. Gary L. Johnson, Ph.D. Aziz Sancar M.D., Ph.D. Beverly S. Mitchell, M.D. 2007 Eric M. Wauson ALL RIGHTS RESERVED ii ABSTRACT Eric M. Wauson: The Regulation of Carbamoyl Phosphate Synthetase-Aspartate Transcarbamoylase-Dihydroorotase (CAD) by Phosphorylation and Protein-Protein Interactions (Under the direction of Lee M. Graves, Ph.D.) Pyrimidines have many important roles in cellular physiology, as they are used in the formation of DNA, RNA, phospholipids, and pyrimidine sugars. The first rate- limiting step in the de novo pyrimidine synthesis pathway is catalyzed by the carbamoyl phosphate synthetase II (CPSase II) part of the multienzymatic complex Carbamoyl phosphate synthetase, Aspartate transcarbamoylase, Dihydroorotase (CAD). CAD gene induction is highly correlated to cell proliferation. Additionally, CAD is allosterically inhibited or activated by uridine triphosphate (UTP) or phosphoribosyl pyrophosphate (PRPP), respectively. The phosphorylation of CAD by PKA and ERK has been reported to modulate the response of CAD to allosteric modulators. While there has been much speculation on the identity of CAD phosphorylation sites, no definitive identification of in vivo CAD phosphorylation sites has been performed. Therefore, we sought to determine the specific CAD residues phosphorylated by ERK and PKA in intact cells. -
T-Cell Receptor
T-cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes,[1] that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.[2] The TCR is composed of two different protein chains (that is, it is a hetero dimer). In humans, in 95% of T cells the TCR consists of an The T-cell receptor complex with alpha (α) chain and a beta (β) chain (encoded by TRA and TRB, TCR-α and TCR-β chains, CD3 and ζ- respectively), whereas in 5% of T cells the TCR consists of gamma chain accessory molecules. and delta (γ/δ) chains (encoded by TRG and TRD, respectively). Identifiers This ratio changes during ontogeny and in diseased states (such as leukemia). It also differs between species. Orthologues of the 4 loci Symbol TCR_zetazeta have been mapped in various species.[3][4] Each locus can produce Pfam PF11628 (http://pfa a variety of polypeptides with constant and variable regions.[3] m.xfam.org/family?ac c=PF11628) When the TCR engages with antigenic peptide and MHC (peptide/MHC), the T lymphocyte is activated through signal InterPro IPR021663 (https://w transduction, that is, a series of biochemical events mediated by ww.ebi.ac.uk/interpro/ associated enzymes, co-receptors, specialized adaptor molecules, entry/IPR021663) and activated or released transcription factors. -
Lecture: 28 TRANSAMINATION, DEAMINATION and DECARBOXYLATION
Lecture: 28 TRANSAMINATION, DEAMINATION AND DECARBOXYLATION Protein metabolism is a key physiological process in all forms of life. Proteins are converted to amino acids and then catabolised. The complete hydrolysis of a polypeptide requires mixture of peptidases because individual peptidases do not cleave all peptide bonds. Both exopeptidases and endopeptidases are required for complete conversion of protein to amino acids. Amino acid metabolism The amino acids not only function as energy metabolites but also used as precursors of many physiologically important compounds such as heme, bioactive amines, small peptides, nucleotides and nucleotide coenzymes. In normal human beings about 90% of the energy requirement is met by oxidation of carbohydrates and fats. The remaining 10% comes from oxidation of the carbon skeleton of amino acids. Since the 20 common protein amino acids are distinctive in terms of their carbon skeletons, amino acids require unique degradative pathway. The degradation of the carbon skeletons of 20 amino acids converges to just seven metabolic intermediates namely. i. Pyruvate ii. Acetyl CoA iii. Acetoacetyl CoA iv. -Ketoglutarate v. Succinyl CoA vi. Fumarate vii. Oxaloacetate Pyruvate, -ketoglutarate, succinyl CoA, fumarate and oxaloacetate can serve as precursors for glucose synthesis through gluconeogenesis.Amino acids giving rise to these intermediates are termed as glucogenic. Those amino acids degraded to yield acetyl CoA or acetoacetate are termed ketogenic since these compounds are used to synthesize ketone bodies. Some amino acids are both glucogenic and ketogenic (For example, phenylalanine, tyrosine, tryptophan and threonine. Catabolism of amino acids The important reaction commonly employed in the breakdown of an amino acid is always the removal of its -amino group. -
DNA DEAMINATION REPAIR ENZYMES in BACTERIAL and HUMAN SYSTEMS Rongjuan Mi Clemson University, [email protected]
Clemson University TigerPrints All Dissertations Dissertations 12-2008 DNA DEAMINATION REPAIR ENZYMES IN BACTERIAL AND HUMAN SYSTEMS Rongjuan Mi Clemson University, [email protected] Follow this and additional works at: https://tigerprints.clemson.edu/all_dissertations Part of the Biochemistry Commons Recommended Citation Mi, Rongjuan, "DNA DEAMINATION REPAIR ENZYMES IN BACTERIAL AND HUMAN SYSTEMS" (2008). All Dissertations. 315. https://tigerprints.clemson.edu/all_dissertations/315 This Dissertation is brought to you for free and open access by the Dissertations at TigerPrints. It has been accepted for inclusion in All Dissertations by an authorized administrator of TigerPrints. For more information, please contact [email protected]. DNA DEAMINATION REPAIR ENZYMES IN BACTERIAL AND HUMAN SYSTEMS A Dissertation Presented to the Graduate School of Clemson University In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Biochemistry by Rongjuan Mi December 2008 Accepted by: Dr. Weiguo Cao, Committee Chair Dr. Chin-Fu Chen Dr. James C. Morris Dr. Gary Powell ABSTRACT DNA repair enzymes and pathways are diverse and critical for living cells to maintain correct genetic information. Single-strand-selective monofunctional uracil DNA glycosylase (SMUG1) belongs to Family 3 of the uracil DNA glycosylase superfamily. We report that a bacterial SMUG1 ortholog in Geobacter metallireducens (Gme) and the human SMUG1 enzyme are not only uracil DNA glycosylases (UDG), but also xanthine DNA glycosylases (XDG). Mutations at M57 (M57L) and H210 (H210G, H210M, H210N) can cause substantial reductions in XDG and UDG activities. Increased selectivity is achieved in the A214R mutant of Gme SMUG1 and G60Y completely abolishes XDG and UDG activity. Most interestingly, a proline substitution at the G63 position switches the Gme SMUG1 enzyme to an exclusive uracil DNA glycosylase. -
Nurse Shark T-Cell Receptors Employ Somatic Hyper- Mutation Preferentially to Alter Alpha/Delta Variable Segments Associated with Alpha Constant Region
Eur. J. Immunol. 2020. 50: 1307–1320 DOI: 10.1002/eji.201948495 Jeannine A. Ott et al. 1307 Basic Adaptive immunity Research Article Nurse shark T-cell receptors employ somatic hyper- mutation preferentially to alter alpha/delta variable segments associated with alpha constant region Jeannine A. Ott1 , Jenna Harrison1, Martin F. Flajnik2 and Michael F. Criscitiello1,3 1 Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA 2 Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore, Baltimore, MD, USA 3 Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Texas A&M University, College Station, TX, USA In addition to canonical TCR and BCR, cartilaginous fish assemble noncanonical TCR that employ various B-cell components. For example, shark T cells associate alpha (TCR- α) or delta (TCR-δ) constant (C) regions with Ig heavy chain (H) variable (V) segments or TCR-associated Ig-like V (TAILV) segments to form chimeric IgV-TCR, and combine TCRδC with both Ig-like and TCR-like V segments to form the doubly rearranging NAR- TCR. Activation-induced (cytidine) deaminase-catalyzed somatic hypermutation (SHM), typically used for B-cell affinity maturation, also is used by TCR-α during selection in the shark thymus presumably to salvage failing receptors. Here, we found that the use of SHM by nurse shark TCR varies depending on the particular V segment or C region used. First, SHM significantly alters alpha/delta V (TCRαδV) segments using TCR αC but not δC. -
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Robyn A Lindley. Medical Research Archives vol 8 issue 8. Medical Research Archives REVIEW ARTICLE Review of the mutational role of deaminases and the generation of a cognate molecular model to explain cancer mutation spectra Author Robyn A Lindley1,2 1Department of Clinical Pathology 2GMDx Genomics Ltd, The Victorian Comprehensive Cancer Centre Level 3 162 Collins Street, Faculty of Medicine, Dentistry & Health Sciences Melbourne VIC3000, AUSTRALIA University of Melbourne, Email: [email protected] 305 Gratton Street, Melbourne, VIC 3000, AUSTRALIA Email: [email protected] Correspondence: Robyn A Lindley, Department of Clinical Pathology, Faculty of Medicine, Dentistry & Health Sciences, University of Melbourne, 305 Gratton Street, Melbourne VIC 3000 AUSTRALIA Mobile: +61 (0) 414209132 Email: [email protected] Abstract Recent developments in somatic mutation analyses have led to the discovery of codon-context targeted somatic mutation (TSM) signatures in cancer genomes: it is now known that deaminase mutation target sites are far more specific than previously thought. As this research provides novel insights into the deaminase origin of most of the somatic point mutations arising in cancer, a clear understanding of the mechanisms and processes involved will be valuable for molecular scientists as well as oncologists and cancer specialists in the clinic. This review will describe the basic research into the mechanism of antigen-driven somatic hypermutation of immunoglobulin variable genes (Ig SHM) that lead to the discovery of TSM signatures, and it will show that an Ig SHM-like signature is ubiquitous in the cancer exome. Most importantly, the data discussed in this review show that Ig SHM-like cancer-associated signatures are highly targeted to cytosine (C) and adenosine (A) nucleotides in a characteristic codon-context fashion. -
Amino Acid Catabolism: Urea Cycle the Urea Bi-Cycle Two Issues
BI/CH 422/622 OUTLINE: OUTLINE: Protein Degradation (Catabolism) Digestion Amino-Acid Degradation Inside of cells Urea Cycle – dealing with the nitrogen Protein turnover Ubiquitin Feeding the Urea Cycle Activation-E1 Glucose-Alanine Cycle Conjugation-E2 Free Ammonia Ligation-E3 Proteosome Glutamine Amino-Acid Degradation Glutamate dehydrogenase Ammonia Overall energetics free Dealing with the carbon transamination-mechanism to know Seven Families Urea Cycle – dealing with the nitrogen 1. ADENQ 5 Steps 2. RPH Carbamoyl-phosphate synthetase oxidase Ornithine transcarbamylase one-carbon metabolism Arginino-succinate synthetase THF Arginino-succinase SAM Arginase 3. GSC Energetics PLP uses Urea Bi-cycle 4. MT – one carbon metabolism 5. FY – oxidases Amino Acid Catabolism: Urea Cycle The Urea Bi-Cycle Two issues: 1) What to do with the fumarate? 2) What are the sources of the free ammonia? a-ketoglutarate a-amino acid Aspartate transaminase transaminase a-keto acid Glutamate 1 Amino Acid Catabolism: Urea Cycle The Glucose-Alanine Cycle • Vigorously working muscles operate nearly anaerobically and rely on glycolysis for energy. a-Keto acids • Glycolysis yields pyruvate. – If not eliminated (converted to acetyl- CoA), lactic acid will build up. • If amino acids have become a fuel source, this lactate is converted back to pyruvate, then converted to alanine for transport into the liver. Excess Glutamate is Metabolized in the Mitochondria of Hepatocytes Amino Acid Catabolism: Urea Cycle Excess glutamine is processed in the intestines, kidneys, and liver. (deaminating) (N,Q,H,S,T,G,M,W) OAA à Asp Glutamine Synthetase This costs another ATP, bringing it closer to 5 (N,Q,H,S,T,G,M,W) 29 N 2 Amino Acid Catabolism: Urea Cycle Excess glutamine is processed in the intestines, kidneys, and liver. -
Epigenetic Regulation in B-Cell Maturation and Its Dysregulation in Autoimmunity
OPEN Cellular and Molecular Immunology (2018) 15, 676–684 www.nature.com/cmi REVIEW Epigenetic regulation in B-cell maturation and its dysregulation in autoimmunity Haijing Wu1, Yaxiong Deng1, Yu Feng1, Di Long1, Kongyang Ma2, Xiaohui Wang2, Ming Zhao1, Liwei Lu2 and Qianjin Lu1 B cells have a critical role in the initiation and acceleration of autoimmune diseases, especially those mediated by autoantibodies. In the peripheral lymphoid system, mature B cells are activated by self or/and foreign antigens and signals from helper T cells for differentiating into either memory B cells or antibody-producing plasma cells. Accumulating evidence has shown that epigenetic regulations modulate somatic hypermutation and class switch DNA recombination during B-cell activation and differentiation. Any abnormalities in these complex regulatory processes may contribute to aberrant antibody production, resulting in autoimmune pathogenesis such as systemic lupus erythematosus. Newly generated knowledge from advanced modern technologies such as next-generation sequencing, single-cell sequencing and DNA methylation sequencing has enabled us to better understand B-cell biology and its role in autoimmune development. Thus this review aims to summarize current research progress in epigenetic modifications contributing to B-cell activation and differentiation, especially under autoimmune conditions such as lupus, rheumatoid arthritis and type 1 diabetes. Cellular and Molecular Immunology advance online publication, 29 January 2018; doi:10.1038/cmi.2017.133 Keywords: -
Deamination Advantages and Disadvantages of Cytidine
Advantages and Disadvantages of Cytidine Deamination Marilia Cascalho This information is current as J Immunol 2004; 172:6513-6518; ; of October 2, 2021. doi: 10.4049/jimmunol.172.11.6513 http://www.jimmunol.org/content/172/11/6513 References This article cites 80 articles, 34 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/172/11/6513.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • 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: by guest on October 2, 2021 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY BRIEF REVIEWS Advantages and Disadvantages of Cytidine Deamination1 Marilia Cascalho2 Cytidine deamination of nucleic acids underlies diversifi- and secreted in the triglyceride-rich chylomicrons that carry di- cation of Ig genes and inhibition of retroviral infection, etary fat (6). A nonedited apo B mRNA is produced in the liver, and thus, it would appear to be vital to host defense. -
A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase.