Chapter 1 Introduction
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Escherichia Coli Responses to a Single DNA Adduct
JOURNAL OF BACTERIOLOGY, Dec. 2000, p. 6598–6604 Vol. 182, No. 23 0021-9193/00/$04.00ϩ0 Copyright © 2000, American Society for Microbiology. All Rights Reserved. Escherichia coli Responses to a Single DNA Adduct GAGAN A. PANDYA,† IN-YOUNG YANG, ARTHUR P. GROLLMAN, AND MASAAKI MORIYA* Laboratory of Chemical Biology, Department of Pharmacological Sciences, SUNY at Stony Brook, Stony Brook, New York 11794-8651 Received 14 June 2000/Accepted 12 September 2000 To study the mechanisms by which Escherichia coli modulates the genotoxic effects of DNA damage, a novel system has been developed which permits quantitative measurements of various E. coli pathways involved in mutagenesis and DNA repair. Events measured include fidelity and efficiency of translesion DNA synthesis, excision repair, and recombination repair. Our strategy involves heteroduplex plasmid DNA bearing a single site-specific DNA adduct and several mismatched regions. The plasmid replicates in a mismatch repair- deficient host with the mismatches serving as strand-specific markers. Analysis of progeny plasmid DNA for linkage of the strand-specific markers identifies the pathway from which the plasmid is derived. Using this approach, a single 1,N6-ethenodeoxyadenosine adduct was shown to be repaired inefficiently by excision repair, to inhibit DNA synthesis by approximately 80 to 90%, and to direct the incorporation of correct dTMP opposite this adduct. This approach is especially useful in analyzing the damage avoidance-tolerance mechanisms. Our results also show that (i) progeny derived from the damage avoidance-tolerance pathway(s) accounts for more than 15% of all progeny; (ii) this pathway(s) requires functional recA, recF, recO, and recR genes, suggesting the mechanism to be daughter strand gap repair; (iii) the ruvABC genes or the recG gene is also required; and (iv) the RecG pathway appears to be more active than the RuvABC pathway. -
1 INTRODUCTION DNA Damage and Types of Repair DNA Is Subject to Various Types of Damage That Can Impair Cellular Function Leadin
INTRODUCTION DNA damage and types of repair DNA is subject to various types of damage that can impair cellular function leading to cell death or carcinogenesis. DNA damage blocks normal cellular processes such as replication and transcription [1, 2]. Should DNA damage persist it can have catastrophic consequences for the cell and for the organism including mutagenesis, cancer, and cell death (i.e. in neurons). DNA damage may come from internal as well as external sources and is associated with various types of genetic diseases and cancers. Therefore DNA repair provides a mechanism to restore DNA nucleotide sequences to the native state. Several DNA repair pathways have been identified including base excision repair (BER), mismatch repair (MMR) and nucleotide excision repair (NER). The type of lesion will dictate which pathway is utilized for repair. For example an N7-methyl guanine residue can only be removed by BER, while a benzopyrene guanine adduct residue can only be removed by NER [3]. Nucleotide Excision Repair Nucleotide Excision Repair (NER) is a versatile DNA repair pathway because of its ability to repair a wide range of nucleotide adducts [4]. NER is responsible for the repair of bulky DNA damage lesions including cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine pyrimidone photoproducts (6-4PPs) caused by UV radiation [3, 5]. NER repairs platinum DNA adducts that are formed by cancer chemotherapeutic drugs such as cisplatin and carboplatin [1, 6, 7]. UV radiation and platinum compounds cause covalent linkage of adjacent thymine or guanine residues respectively. Aromatic 1 hydrocarbons, as found in cigarette smoke, cause guanine adducts that also require NER for their removal. -
Slow Repair of Bulky DNA Adducts Along the Nontranscribed Strand of the Human P53 Gene May Explain the Strand Bias of Transversion Mutations in Cancers
Oncogene (1998) 16, 1241 ± 1247 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 Slow repair of bulky DNA adducts along the nontranscribed strand of the human p53 gene may explain the strand bias of transversion mutations in cancers Mikhail F Denissenko1, Annie Pao2, Gerd P Pfeifer1 and Moon-shong Tang2 1Beckman Research Institute, City of Hope, Duarte, California 91010; 2University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA Using UvrABC incision in combination with ligation- cancer development (Hollstein et al., 1991, 1996; Jones mediated PCR (LMPCR) we have previously shown that et al., 1991; Harris and Hollstein, 1993; Greenblatt et benzo(a)pyrene diol epoxide (BPDE) adduct formation al., 1994; Harris, 1996; Ruddon, 1995). along the nontranscribed strand of the human p53 gene is The p53 mutations found in human cancers are of highly selective; the preferential binding sites coincide various types, and occur at dierent sequences with the major mutation hotspots found in human lung (Greenblatt et al., 1994; Hollstein et al., 1996). More cancers. Both sequence-dependent adduct formation and than 200 mutated codons of the p53 gene have been repair may contribute to these mutation hotspots in identi®ed in various human cancers, and the types of tumor tissues. To test this possibility, we have extended mutations often seem to bear the signature of the our previous studies by mapping the BPDE adduct etiological agent (Greenblatt et al., 1994; Hollstein et distribution in the transcribed strand of the p53 gene and al., 1996). One of the most notable examples is lung quantifying the rates of repair for individual damaged cancer. -
Chemical Synthesis, Characterization and Biological Evaluation of Methylation and Glycation Dna Adducts
University of Rhode Island DigitalCommons@URI Open Access Dissertations 2019 CHEMICAL SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF METHYLATION AND GLYCATION DNA ADDUCTS Qi Tang University of Rhode Island, [email protected] Follow this and additional works at: https://digitalcommons.uri.edu/oa_diss Recommended Citation Tang, Qi, "CHEMICAL SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF METHYLATION AND GLYCATION DNA ADDUCTS" (2019). Open Access Dissertations. Paper 844. https://digitalcommons.uri.edu/oa_diss/844 This Dissertation is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Open Access Dissertations by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. CHEMICAL SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF METHYLATION AND GLYCATION DNA ADDUCTS BY QI TANG A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN PHARMACEUTICAL SCIENCES UNIVERSITY OF RHODE ISLAND 2019 DOCTOR OF PHILOSOPHY DISSERTATION OF QI TANG APPROVED: Dissertation Committee: Major Professor Deyu Li Bongsup Cho Gongqin Sun Nasser H. Zawia DEAN OF THE GRADUATE SCHOOL UNIVERSITY OF RHODE ISLAND 2019 ABSTRACT The integrity of genomic DNA is constantly challenged by endogenous and environmental agents with the formation of DNA adducts. Some of these adducts are toxic and mutagenic to replication, thus potentially leading to cancer and other genetic diseases. To counteract the undesired DNA modifications from damaging agents, cells have evolved a number of repair pathways, such as base-excision repair, nucleotide-excision repair, mismatch repair, and direct reversal repair, to restore the intact DNA. However, DNA repair is not always efficient, there are many interfering factors, such as inherited deficiency in DNA repair pathways, or the abnormal uptake of substance with inhibitory effects to DNA repair enzymes that may result in the accumulation of DNA adducts. -
Targeted Mutations Induced by a Single Acetylaminofluorene DNA
Proc. Nati. Acad. Sci. USA Vol. 85, pp. 1586-1589, March 1988 Genetics Targeted mutations induced by a single acetylaminofluorene DNA adduct in mammalian cells and bacteria (shuttle vector/mutagenesis) MASAAKI MORIYA*, MASARU TAKESHITA*, FRANCIS JOHNSON*, KEITH PEDENt, STEPHEN WILL*, AND ARTHUR P. GROLLMAN *Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794; and tHoward Hughes Medical Institute Laboratory, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205 Communicated by Richard B. Setlow, November 2, 1987 ABSTRACT Mutagenic specificity of 2-acetylamino- lems were obviated by initiating mutagenesis with a defined fluorene (AAF) has been established in mammalian cells and DNA adduct introduced at a specific site in the genome and several strains of bacteria by using a shuttle plasmid vector by detecting the full spectrum of mutations by oligodeoxy- containing a single N-(deoxyguanosin-8-yl)acetylaminofluo- nucleotide hybridization. rene (C8-dG-AAF) adduct. The nucleotide sequence of the Viral and plasmid vectors containing specifically located gene conferring tetracycline resistance was modified by con- DNA adducts have been described (5-8); some ofthese have servative codon replacement so as to accommodate the se- been tested for mutagenic properties in bacteria (8-10). We quence d(CCTTCGCTAC) flanked by two restriction sites, have constructed a shuttle plasmid containing a single Bsm I and Xho I. The corresponding synthetic oligodeoxynu- "bulky" adduct, N-(deoxyguanosin-8-yl)acetylaminofluo- cleotide underwent reaction with 2-(N-acetoxy-N-acetylamino)- rene (C8-dG-AAF). This modified plasmid was allowed to fluorene (AAAF), forming a single dG-AAF adduct. -
Health Effects of Chemical Mixtures: Benzo(A)Pyrene and Arsenic
Health Effects of Chemical Mixtures: Benzo[a]pyrene and Arsenic Hasmik Hakobyan, Elizabeth Vaccaro and Hollie Migdol Department of Environmental & Occupational Health, California State University, Northridge Abstract Routes of Exposure Metabolism of Benzo[a]pyrene and Arsenic Arsenic and benzo[a]pyrene (BaP) are ubiquitous compounds commonly found throughout the environment. This poster is a review of the current literature examining the combined effects of arsenic and BaP to determine the mechanism of their synergistic qualities. Being exposed to both arsenic and BaP simultaneously in the environment is very likely. Vehicle exhaust, volcanoes, cigarette smoke, air pollution, industrial processes contaminated water and charred meats can contribute to the co-exposure to arsenic and BaP. The carcinogenicity of BaP occurs subsequent to the metabolic activation of the compound resulting in DNA damage via DNA-adduct formation. The literature indicates that the co-exposure to arsenic and BaP causes a synergistic reaction between to the two compounds, as arsenic potentiates BaP-DNA adducts. BaP DNA adduct formation. [18] Introduction Arsenic occurs in the environment naturally and it is Arsenic manmade. Arsenic sources are algaecides, mechanical cotton harvesting, glass manufacturing, herbicides, and nonferrous Dermal: Dermal exposure may lead to illness, but to a lesser extent alloys [2]. Arsenic trioxide may be found in pesticides and than ingestion or inhalation. [4] [9] defoliants and as a contaminant of moonshine whiskey [2]. Presently, arsenic is widely used in the electronics industry in Ingestion: Main intake of arsenic is through ingestion of food the form of gallium arsenide and arsine gas as components in containing arsenic. -
Processed Meat Grilled Meat Bacon Air Pollution Car Exhaust
Diet and Lifestyle Factors in Cancer Risk Robert J. Turesky, Ph.D. Professor Masonic Chair in Cancer Causation Masonic Cancer Center Department of Medicinal Chemistry Disclosure ⚫ I have no actual or potential conflict of interest in relation to this program/presentation. A lot of research focuses on agents that can cause cancer Drug Safety "Alle Dinge sind Gift und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist.” ( "All things are poison and nothing is without poison; only the dose makes a thing not a poison.” ) Paracelsus 1493-1541 Paracelsus (born Philippus Aureolus Theophrastus Bombastus von Hohenheim) Swiss physician, alchemist Diet and cancer: many cancers are caused by lifestyle factors, not genetics • Change in phyto- N-nitroso compounds estrogen profiles from from salted fish, plants, soy? pickled vegetables (nitrates) • Exposures to “new” carcinogens What are carcinogens? Carcinogens generally cause damage after repeated or long-duration exposure. They may not have immediate apparent harmful effects, with cancer developing only after a long latency period. Dose: amount and duration of exposure. The lower the dose the least likely you are to develop cancer or related diseases. Carcinogens increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, by forming DNA adducts, which interfere with biological processes, and induce mutations resulting in the uncontrolled, malignant division, ultimately leading to the formation of tumors. Chemicals formed endogenously, i.e. -
Excision of Oxidatively Generated Guanine Lesions by Competitive DNA Repair Pathways
International Journal of Molecular Sciences Review Excision of Oxidatively Generated Guanine Lesions by Competitive DNA Repair Pathways Vladimir Shafirovich * and Nicholas E. Geacintov Chemistry Department, New York University, New York, NY 10003-5180, USA; [email protected] * Correspondence: [email protected] Abstract: The base and nucleotide excision repair pathways (BER and NER, respectively) are two major mechanisms that remove DNA lesions formed by the reactions of genotoxic intermediates with cellular DNA. It is generally believed that small non-bulky oxidatively generated DNA base modifi- cations are removed by BER pathways, whereas DNA helix-distorting bulky lesions derived from the attack of chemical carcinogens or UV irradiation are repaired by the NER machinery. However, existing and growing experimental evidence indicates that oxidatively generated DNA lesions can be repaired by competitive BER and NER pathways in human cell extracts and intact human cells. Here, we focus on the interplay and competition of BER and NER pathways in excising oxidatively generated guanine lesions site-specifically positioned in plasmid DNA templates constructed by a gapped-vector technology. These experiments demonstrate a significant enhancement of the NER yields in covalently closed circular DNA plasmids (relative to the same, but linearized form of the same plasmid) harboring certain oxidatively generated guanine lesions. The interplay between the BER and NER pathways that remove oxidatively generated guanine lesions are reviewed and discussed in terms of competitive binding of the BER proteins and the DNA damage-sensing NER Citation: Shafirovich, V.; Geacintov, factor XPC-RAD23B to these lesions. N.E. Excision of Oxidatively Generated Guanine Lesions by Keywords: DNA damage; base excision repair; nucleotide excision repair; oxidative stress; reactive Competitive DNA Repair Pathways. -
Derived Exocyclic Guanine Adducts by the #-Ketoglutarate/Fe(II) Dioxygenase Alkb
Mechanism of Repair of Acrolein- and Malondialdehyde- Derived Exocyclic Guanine Adducts by the #-Ketoglutarate/Fe(II) Dioxygenase AlkB The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Singh, Vipender, Bogdan I. Fedeles, Deyu Li, James C. Delaney, Ivan D. Kozekov, Albena Kozekova, Lawrence J. Marnett, Carmelo J. Rizzo, and John M. Essigmann. “Mechanism of Repair of Acrolein- and Malondialdehyde-Derived Exocyclic Guanine Adducts by the α-Ketoglutarate/Fe(II) Dioxygenase AlkB.” Chemical Research in Toxicology 27, no. 9 (September 15, 2014): 1619–1631. © 2014 American Chemical Society As Published http://dx.doi.org/10.1021/tx5002817 Publisher American Chemical Society (ACS) Version Final published version Citable link http://hdl.handle.net/1721.1/99406 Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Article pubs.acs.org/crt Mechanism of Repair of Acrolein- and Malondialdehyde-Derived Exocyclic Guanine Adducts by the α‑Ketoglutarate/Fe(II) Dioxygenase AlkB † ‡ § ⊥ † ‡ § ⊥ † ‡ § ⊥ † ‡ § # ∥ Vipender Singh, , , , Bogdan I. Fedeles, , , , Deyu Li, , , , James C. Delaney, , , , Ivan D. Kozekov, ∥ ∥ ∥ † ‡ § Albena Kozekova, Lawrence J. Marnett, Carmelo J. Rizzo, and -
Usepa: Toxicological Review of Trichloroacetic Acid
DRAFT - DO NOT CITE OR QUOTE EPA/635/R-09/003A www.epa.gov/iris TOXICOLOGICAL REVIEW OF TRICHLOROACETIC ACID (CAS No. 76-03-9) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2009 NOTICE This document is an External Review draft. This information is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. It is being circulated for review of its technical accuracy and science policy implications. U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document is a preliminary draft for review purposes only. This information is distributed solely for the purpose of pre-dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ii DRAFT - DO NOT CITE OR QUOTE CONTENTS—TOXICOLOGICAL REVIEW OF TRICHLOROACETIC ACID (CAS No. 76-03-9) LIST OF TABLES .......................................................................................................................... v LIST OF FIGURES ....................................................................................................................... vi LIST OF ABBREVIATIONS -
Oxaliplatin–DNA Adducts As Predictive Biomarkers of FOLFOX
Published OnlineFirst February 6, 2020; DOI: 10.1158/1535-7163.MCT-19-0133 MOLECULAR CANCER THERAPEUTICS | COMPANION DIAGNOSTIC, PHARMACOGENOMIC, AND CANCER BIOMARKERS Oxaliplatin–DNA Adducts as Predictive Biomarkers of FOLFOX Response in Colorectal Cancer: A Potential Treatment Optimization Strategy Maike Zimmermann1,2, Tao Li1, Thomas J. Semrad1,3, Chun-Yi Wu4, Aiming Yu4, George Cimino2, Michael Malfatti5, Kurt Haack5, Kenneth W. Turteltaub5, Chong-xian Pan1,6,7, May Cho1, Edward J. Kim1, and Paul T. Henderson1,2 ABSTRACT ◥ FOLFOX is one of the most effective treatments for advanced enabled quantification of oxaliplatin–DNA adduct level with accel- colorectal cancer. However, cumulative oxaliplatin neurotoxicity erator mass spectrometry (AMS). Oxaliplatin–DNA adduct forma- often results in halting the therapy. Oxaliplatin functions predom- tion was correlated with oxaliplatin cytotoxicity for each cell line as inantly via the formation of toxic covalent drug–DNA adducts. We measured by the MTT viability assay. Six colorectal cancer hypothesize that oxaliplatin–DNA adduct levels formed in vivo in patients received by intravenous route a diagnostic microdose peripheral blood mononuclear cells (PBMC) are proportional to containing [14C]oxaliplatin prior to treatment, as well as a second tumor shrinkage caused by FOLFOX therapy. We further hypoth- [14C]oxaliplatin dose during FOLFOX chemotherapy, termed a esize that adducts induced by subtherapeutic “diagnostic micro- “therapeutic dose.” Oxaliplatin–DNA adduct levels from PBMC doses” are proportional to those induced by therapeutic doses correlated significantly to mean tumor volume change of evaluable and are also predictive of response to FOLFOX therapy. These target lesions (5 of the 6 patients had measurable disease). Oxali- hypotheses were tested in colorectal cancer cell lines and a pilot platin–DNA adduct levels were linearly proportional between clinical study. -
Redalyc.THEORETICAL STUDY of the MALONDIALDEHYDE
Vitae ISSN: 0121-4004 [email protected] Universidad de Antioquia Colombia QUIJANO P., Silvia; NOTARIO B., Rafael; QUIJANO T., Jairo; RAMÍREZ A., Luz A.; VÉLEZ O., Ederley; GIL G., Maritza A. THEORETICAL STUDY OF THE MALONDIALDEHYDE-ADDUCTS FORMED BY REACTION WITH DNA-BASES Vitae, vol. 11, núm. 1, 2004, pp. 5-12 Universidad de Antioquia Medellín, Colombia Available in: http://www.redalyc.org/articulo.oa?id=169818259002 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative 5 VITAE, REVISTA DE LA FACULTAD DE QUÍMICA FARMACÉUTICA ISSN 0121-4004 Volumen 11 número 1, año 2004. Universidad de Antioquia, Medellín - Colombia. págs. 5-12 THEORETICAL STUDY OF THE MALONDIALDEHYDE- ADDUCTS FORMED BY REACTION WITH DNA-BASES ESTUDIO TEÓRICO DE LOS ADUCTOS-MALONDIALDEHÍDO FORMADOS POR LA REACCIÓN CON BASES ADN Silvia QUIJANO P.,1* Rafael NOTARIO B.,2 Jairo QUIJANO T.,3 Luz A. RAMÍREZ A.,3 Ederley VÉLEZ O.3 y Maritza A. GIL G.3 ABSTRACT Malondialdehyde (MDA) is a major genotoxic carbonyl compound generated by lipid peroxidation and is also a by-product of the arachidonic acid metabolism in the synthesis of prostaglandins. MDA has been shown to be mutagenic in bacterial and mammalian systems and carcinogenic in rodents. Besides, it is known that MDA reacts with DNA to form adducts with deoxyguanosine, dG, deoxyadenosine, dA, and deoxycytidine, dC: M1G, M1A and M1C, respectively. In this paper we present a density functional theoretical study of the several nucleophilic additions followed by eliminations of MDA with dG, dA, and dC.