DOCSLIB.ORG

Generation, Biological Consequences and Repair Mechanisms of Cytosine Deamination in DNA

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Generation, Biological Consequences and Repair Mechanisms of Cytosine Deamination in DNA J. Radiat. Res., 50, 19–26 (2009) Review Generation, Biological Consequences and Repair Mechanisms of Cytosine Deamination in DNA# Shin-Ichiro YONEKURA, Nobuya NAKAMURA, Shuji YONEI and Qiu-Mei ZHANG-AKIYAMA* Deamination of Cytosine/Uracil/Transition Mutations/Base Excision Repair/Uracil-DNA Glycosylase/ dUTPase. Base moieties in DNA are spontaneously threatened by naturally occurring chemical reactions such as deamination, hydrolysis and oxidation. These DNA modifications have been considered to be major causes of cell death, mutations and cancer induction in organisms. Organisms have developed the DNA base excision repair pathway as a defense mechanism to protect them from these threats. DNA glycosy- lases, the key enzyme in the base excision repair pathway, are highly conserved in evolution. Uracil constantly occurs in DNA. Uracil in DNA arises by spontaneous deamination of cytosine to generate pro- mutagenic U:G mispairs. Uracil in DNA is also produced by the incorporation of dUMP during DNA replication. Uracil-DNA glycosylase (UNG) acts as a major repair enzyme that protects DNA from the deleterious consequences of uracil. The first UNG activity was discovered in E. coli in 1974. This was also the first discovery of base excision repair. The sequence encoded by the ung gene demonstrates that the E. coli UNG is highly conserved in viruses, bacteria, archaea, yeast, mice and humans. In this review, we will focus on central and recent findings on the generation, biological consequences and repair mechanisms of uracil in DNA and on the biological significance of uracil-DNA glycosylase. ination by the complementary strand.1,4) Pro-mutagenic G:U GENERATION, BIOLOGICAL CONSEQUENCES mispairs cause G:C to A:T transition mutations, if not repaired OF CYTOSINE DEAMINATION prior to the next round of DNA replication.1,3–5,7) Deamination of cytosine in cyclobutane dimers is markedly faster than that 1,4,6) DNA reacts continually with H2O (hydrolysis) and reactive of cytosine in other sequences, and has been implicated in oxygen species, resulting in multiple spontaneous DNA UV-mutagenesis in both bacteria and mammalian cells.1,8,9) modifications.1–6) Four bases normally present in DNA contain Uracil also occurs in DNA through incorporation of exocyclic amino groups. The loss of these amino groups dUMP instead of dTMP by DNA polymerases during repli- (deamination) in cytosine, adenine, guanine and 5- cation.1,3–5,10,11) Incorporated dUMP forms U:A base pairs that methylcytosine occurs spontaneously and results in the are not directly mutagenic, but may be cytotoxic.1,3–5,12) conversion to uracil, hypoxanthine, xanthine and thymine, Substitution of thymine with uracil is a major source of respectively.3,4,6) The deamination of cytosine (Fig. 1) is endogenous abasic (AP) sites,12) which may mediate the cyto- estimated to result in 100–500 uracil residues per mammalian toxicity of uracil in DNA. dUTP is a normally occurring inter- genome per day.1,4–6) Cytosine deamination in single-stranded DNA is reported to be 200–300 times faster than that in double- stranded DNA.1,3–6) Single-stranded regions in replication forks and transcription bubbles are not protected from deam- *Corresponding author: Phone: +075-753-4097, Fax: +075-753-4087, E-mail: [email protected] Department of Biological Sciences, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan. #Foot-note: Translated and modified from Radiat. Biol. Res. Comm. Vol. 42; 132–146 (2007, in Japanese). doi:10.1269/jrr.08080 Fig. 1. Deamination of the 4 position of cytosine generates uracil. J. Radiat. Res., Vol. 50, No. 1 (2009); http://jrr.jstage.jst.go.jp 20 S.-I. Yonekura et al. mediate in nucleotide metabolism, but its level is kept low by U:A mispairs in DNA.1,3–5,18) Far more uracil residues than an efficient dUTPase (DUT). The pyrophosphatase activity of normal are incorporated into DNA in the dut mutant cells, dUTPase hydrolyzes dUTP to dUMP and PPi, which prevents as described above. The increased levels of uracil in DNA the incorporation of dUMP into DNA.1,3–5) Uracil incorpora- are also reduced by UNG. UNG does not possess associated tion into DNA is presumed to occur on an average of one per AP lyase activity, and the resultant AP sites are processed by 2,000–3,000 nucleotides in the dut mutant deficient in AP endonucleases.1,3–5,22) E. coli cells deficient in dUTPase dUTPase. Tye et al. (1978) reported that E. coli mutants defec- (dut) and exonuclease III (the major AP endonuclease in E. tive in both the dut and ung genes accumulate more uracil in coli, xthA) are therefore not viable.15) their DNA.10) Lari et al. (2006) determined the steady-state In E. coli, there are some uracil-removing enzymatic levels of uracil residues in DNA using the Ung-ARP assay.13) activities other than UNG. For example, mismatch-specific The uracil levels are 3,000–8,000/106 nucleotides in the ung uracil-DNA glycosylase (MUG) also removes uracil from dut mutant of E. coli, in contract to about 1/106 nucleotides in U:G mismatches.1,3-5) MUG has been thought to be a backup the wild-type strain (ung+ dut+).12,13) enzyme of UNG.3–5,23) MUG can act on mutagenic alkylated The frequency of spontaneous G:C to A:T transitions bases and 3,N4-ethenocytosine.23) significantly increases in E. coli and S. cerevisiae ung Endonuclease V (Nfi) in E. coli selectively cleaves mutants deficient in UNG.1,3–5,14–16) Increased spontaneous untreated single-stranded DNA and duplex DNA containing mutations in the ung mutants were also observed using λ uracil, hypoxanthine and mismatches.24–26) When the nfi bacteriophage.16) When λ phage is treated with bisulfite, an mutant is treated with nitrous acid, it exhibits high frequencies agent known to cause cytosine deamination in DNA, the of A:T to G:C and G:C to A:T transition mutations.11,24–26) frequency of clear-plaque mutations is increased an Nitrous acid causes deamination of adenine and converts additional 20-fold when the phage is grown on E. coli ung adenine to hypoxanthine.26) The resulting deoxyinosine mutant rather than on ung+ cells.16) On the other hand, the (hypoxanthine deoxyribonucleoside) induces A:T to G:C frequency of bisulfite-induced mutations in E. coli ung transitions through pairing with cytosine, resulting in possible mutant is almost equal to that in the wild-type strain. The targets for Nfi.27) The Nfi enzyme was originally identified authors suggested that cellular uracil DNA glycosylase as a deoxyinosine 3’-endonuclease that cleaves DNA near might be inactivated by the bisulfite treatment.16) dIMP residues, mismatched bases, urea residues and AP sites.24–26) While nitrous acid causes deamination of cytosine URACIL-DNA GLYCOSYLASES IN BACTERIA, to generate uracil, it does not play the causative role in YEAST AND NEMATODE increased G:C to T:A transitions in the nfi mutant cells, because the ung mutant does not affect the transition fre- Endogenous DNA damage is mainly repaired by the base quency induced by nitrous acid. Schounten and Weiss excision repair pathway. The repair pathway is initiated by (1999) suggested a role for endonuclease V in the removal monofunctional DNA glycosylases that only remove the of deaminated guanine (i.e., xanthine) from DNA.26) altered base (e.g., uracil-DNA glycosylase) or bifunctional Bacteriophage PBS2 normally contains uracil instead of glycosylases that in addition to base removal incise the thymine in its DNA. Bacillus subtilis is the natural host for resulting apurinic/apyrimidinic (AP) site by an associated this bacteriophage. As indicated by the high level of UNG AP lyase activity (e.g., endonuclease III).1,3,4,17–19) The uracil activity present in extracts from B. subtilis, PBS2 would be N-glycosylase activity (UNG) of E. coli was the first DNA easily inactivated in B. subtilis. Following infection, the glycosylase to be discovered in a search for activities that phage induces the expression of PBS2 DNA encoded uracil- would repair uracil in DNA.20,21) UNG recognizes uracil in DNA glycosylase inhibitor (Ugi).28,29) Ugi forms a stable 1:1 DNA and removes it from the DNA backbone as the first complex with Ung and inactivates it. Ugi specifically inhib- step of the base excision repair pathway for uracil.20) The its the uracil-DNA glycosylase activity of UNG family-1 open reading frame of the ung gene in E. coli encodes a pro- protein.3–5,28,29) Therefore, Ugi is often used to examine tein of 229 amino acids. The purified enzyme from E. coil whether or not the biological effect of uracil-removing activ- hydrolyzes the N-glycosylic bond between uracil and deox- ities is due to the family 1 uracil-DNA glycosylase.3,30) yribose, thus releasing a free uracil and leaving an AP site In yeast, UNG homologs function in both the nucleus and in DNA.3–5) AP endonucleases recognize the resultant AP mitochondria. The ung-1 mutant of S. cerevisiae shows a site and cleave the phosphodiester backbone 5’ to the AP high frequency of spontaneous mutations in the nuclear site. This step is followed by DNA repair synthesis by DNA SUP4-o gene31) and mitochondrial petite loci, compared polymerases, and the DNA nick is finally rejoined by the with the isogenic wild-type cells.32) Deletion of the dut-1 action of DNA ligase.2–5) UNG of E. coli can remove roughly gene that encodes dUTPase is lethal in S. cerevisiae owing 800 uracil residues from DNA per minute and is present at to cell cycle arrest.4,33,34) However, the viability of the dut-1 about 300 molecules per cell.4) strain is restored when the ung gene is disrupted simulta- UNG of E.
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Theoretical Studies of DNA Base Deamination. 2. Ab Initio Study of DNA Base Diazonium Ions and of Their Linear, Unimolecular Dediazoniation Paths†,§
    6108 J. Am. Chem. Soc. 1999, 121, 6108-6119 Theoretical Studies of DNA Base Deamination. 2. Ab Initio Study of DNA Base Diazonium Ions and of Their Linear, Unimolecular Dediazoniation Paths†,§ Rainer Glaser,* Sundeep Rayat, Michael Lewis, Man-Shick Son, and Sarah Meyer Contribution from the Department of Chemistry, UniVersity of Missouri-Columbia, Columbia, Missouri 65211 ReceiVed NoVember 30, 1998 Abstract: Deamination of the DNA bases cytosine, adenine, and guanine can be achieved by way of diazotization and the diazonium ions of the DNA bases are considered to be the key intermediates. The DNA base diazonium ions are thought to undergo nucleophilic substitution by water or other available nucleophiles. Cross-link formation is thought to occur if the amino group of a neighboring DNA base acts as the nucleophile. All mechanistic hypotheses invoking DNA base diazonium ions are based on product analyses and deduction and analogy to the chemistry of aromatic primary amines while none of the DNA base diazonium ions has been observed or characterized directly. We report the results of an ab initio study of the diazonium ions 1, 3, and 5, derived by diazotization of the DNA bases cytosine, adenine, and guanine, respectively, and of their unimolecular dediazoniations to form the cations 2, 4, and 6, respectively. The dediazoniation paths of two iminol tautomers of 1 and 5 also were considered. The unimolecular dediazoniation paths were explored and none of these corresponds to a simple Morse-type single-minimum potential. Instead, double-minimum potential curves are found in most cases, that is, minima exist both for a classical diazonium ion structure (a structure) as well as for an electrostatically bound cation-dinitrogen complex (b structure), and these minima are separated by a transition state structure (c structure).
    [Show full text]
  • Reading Targeted DNA Damage in the Active
    Reading targeted DNA damage in the active demethylation pathway: role of accessory domains of eukaryotic AP endonucleases and thymine-DNA glycosylases Alexander Popov, Inga Grin, Antonina Dvornikova, Bakhyt Matkarimov, Regina Groisman, Murat Saparbaev, Dmitry Zharkov To cite this version: Alexander Popov, Inga Grin, Antonina Dvornikova, Bakhyt Matkarimov, Regina Groisman, et al.. Reading targeted DNA damage in the active demethylation pathway: role of accessory domains of eukaryotic AP endonucleases and thymine-DNA glycosylases. Journal of Molecular Biology, Elsevier, 2020, 432 (6), pp.1747-1768. 10.1016/j.jmb.2019.12.020. hal-03060641 HAL Id: hal-03060641 https://hal.archives-ouvertes.fr/hal-03060641 Submitted on 14 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. *Manuscript Click here to view linked References Reading targeted DNA damage in the active demethylation 1 pathway: role of accessory domains of eukaryotic AP endonucleases 2 3 4 and thymine-DNA glycosylases 5 1 1,2 1,2 6 Alexander V. Popov , Inga R. Grin , Antonina P. Dvornikova
    [Show full text]
  • The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer
    International Journal of Molecular Sciences Review The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer Sripriya Raja 1,2 and Bennett Van Houten 1,2,3,* 1 Molecular Pharmacology Graduate Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; [email protected] 2 UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA 3 Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA * Correspondence: [email protected]; Tel.: +1412-623-7762; Fax: +1-412-623-7761 Abstract: Single-strand selective monofunctional uracil DNA glycosylase 1 (SMUG1) works to remove uracil and certain oxidized bases from DNA during base excision repair (BER). This review provides a historical characterization of SMUG1 and 5-hydroxymethyl-20-deoxyuridine (5-hmdU) one important substrate of this enzyme. Biochemical and structural analyses provide remarkable insight into the mechanism of this glycosylase: SMUG1 has a unique helical wedge that influences damage recognition during repair. Rodent studies suggest that, while SMUG1 shares substrate specificity with another uracil glycosylase UNG2, loss of SMUG1 can have unique cellular phenotypes. This review highlights the multiple roles SMUG1 may play in preserving genome stability, and how the loss of SMUG1 activity may promote cancer. Finally, we discuss recent studies indicating SMUG1 has moonlighting functions beyond BER, playing a critical role in RNA processing including the RNA component of telomerase. Keywords: DNA damage; base excision repair; SMUG1; 5-hmdU; cancer Citation: Raja, S.; Van Houten, B. The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer. Int. J. Mol. Sci.
    [Show full text]
  • Biosynthesis of Urea
    E-content M.Sc. Zoology (Semester II) CC7- Biochemistry Unit: 3.4 Biosynthesis of Urea Dr Gajendra Kumar Azad Assistant Professor Post Graduate Department of Zoology Patna University, Patna Email: [email protected] 1 Terrestrial organisms have evolved mechanisms to excrete nitrogenous wastes. The animals must detoxify ammonia by converting it into a relatively nontoxic form such as urea or uric acid. Mammals, including humans, produce urea, whereas reptiles and many terrestrial invertebrates produce uric acid. The urea cycle, also called the ornithine cycle, was discovered by Hans Krebs at the University of Freiburg in Germany, in 1932. Biosynthesis of Urea takes place in following four stages 1. Transamination 2. Oxidative deamination of glutamate 3. Ammonia transport 4. Reactions of the Urea cycle 2 Over all nitrogen flow in amino-acid catabolism 3 1. Transamination It is a process of transferring amino groups from one molecule to another. There is no formation and no excretion of ammonia, thus no net change in the nitrogen amount of body. The raw materials for transmination are α-amino acid and α-ketoglutarate. The reaction is catalysed by the enzyme aminotranferase (transaminase) which requires pyridoxal phosphate as a prosthetic group. All transaminases contain this prosthetic group which derives from pyridoxine a water soluble vitamin also known as vitamin B6. The amino group from amino acids is temporarily uptaken by the pyridoxal phosphate as pyridoxamine phosphate prior to its donation to an α-ketoacid. All amino acids except lysine, threonine, proline and hydroxyproline participate in transamination process. 4 Transamination reaction In many aminotransferase reactions, α-ketoglutarate is the amino group acceptor.
    [Show full text]
  • Specific Hnrnp Cofactors for Activation-Induced Cytidine Deaminase
    Identification of DNA cleavage- and recombination- specific hnRNP cofactors for activation-induced cytidine deaminase Wenjun Hu1, Nasim A. Begum1, Samiran Mondal, Andre Stanlie, and Tasuku Honjo2 Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan Contributed by Tasuku Honjo, March 31, 2015 (sent for review February 20, 2015) Activation-induced cytidine deaminase (AID) is essential for anti- family, which is related to ancestral AID-like enzymes, PmCDA1 body class switch recombination (CSR) and somatic hypermutation and PmCDA2, expressed in the lamprey (13, 14). Although most (SHM). AID originally was postulated to function as an RNA- of these related proteins are predicted to be involved in cytidine editing enzyme, based on its strong homology with apolipopro- deamination, their targets and the molecular mechanisms are not tein B mRNA-editing enzyme, catalytic polypeptide 1 (APOBEC1), fully elucidated (15). The best-characterized AID-like enzyme is the enzyme that edits apolipoprotein B-100 mRNA in the presence APOBEC1, an RNA-editing enzyme that catalyzes the site-spe- of the APOBEC cofactor APOBEC1 complementation factor/APOBEC cific deamination of C to U at position 6666 of the apolipoprotein complementation factor (A1CF/ACF). Because A1CF is structurally B-100 (APO B-100) mRNA, generating a premature stop codon similar to heterogeneous nuclear ribonucleoproteins (hnRNPs), we (16–18). The edited mRNA, referred to as “APOB-48,” encodes investigated the involvement of several well-known hnRNPs in AID the triglyceride carrier protein, a truncated product of the LDL function by using siRNA knockdown and clustered regularly inter- carrier protein, which is encoded by APO B-100 mRNA.
    [Show full text]
  • Activation-Induced Cytidine Deaminase Hypermutation in The
    Characterization of Ig Gene Somatic Hypermutation in the Absence of Activation-Induced Cytidine Deaminase This information is current as Nancy S. Longo, Colleen L. Satorius, Alessandro Plebani, of September 29, 2021. Anne Durandy and Peter E. Lipsky J Immunol 2008; 181:1299-1306; ; doi: 10.4049/jimmunol.181.2.1299 http://www.jimmunol.org/content/181/2/1299 Downloaded from References This article cites 41 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/181/2/1299.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Characterization of Ig Gene Somatic Hypermutation in the Absence of Activation-Induced Cytidine Deaminase1 Nancy S. Longo,* Colleen L. Satorius,* Alessandro Plebani,† Anne Durandy,‡§¶ and Peter E. Lipsky2* ؍ A/G, Y ؍ A/T, R ؍ Somatic hypermutation (SHM) of Ig genes depends upon the deamination of C nucleotides in WRCY (W C/T) motifs by activation-induced cytidine deaminase (AICDA).
    [Show full text]
  • DNA Base Excision Repair: Mutation Induction and Novel Functions
    DNA Base Excision Repair: Mutation Induction and Novel Functions by Izaskun Muruzábal-Lecumberri Thesis submitted in fulfillment of the requirements for the degree of PHILOSOPHIAE DOCTOR (PhD) Faculty of Science and Technology Department for Mathematics and Natural Sciences Centre for Organelle Research (CORE) 2015 University of Stavanger N-4036 Stavanger NORWAY www.uis.no © 2015 Izaskun Muruzábal-Lecumberri ISBN: 978-82-7644-608-1 ISSN: 1890-1387 PhD thesis no. 258 Abstract DNA is susceptible to chemical modifications corrupting its cellular information processing function, necessitating correction of such modifications. Cells are formed mostly by water – giving rise to hydrolytic reactions – and aerobic metabolism is a source of reactive oxygen species (ROS) – causing oxidation. Deamination of cytosine to uracil is an example of the former and oxidation of thymine to 5-formyluracil (f5U) is an example of the latter. In order to avoid the incorporation of wrong nucleosides into DNA, f5U must be eliminated and substituted by the correct base. The main mechanism for the repair of f5U is the base excision repair (BER) pathway, in which specific glycosylases recognize the damage and excise it from its ribose residue. Several glycosylases have been found to be involved in the repair of f5U in Escherichia coli, where 3-methyladenine DNA glycosylase II (AlkA) may be the most important. However, here we present evidence to indicate that the nucleotide excision repair protein UvrA is also involved in the repair of f5U, although the mechanism has yet to be elucidated. Interestingly, we have found that the AlkA glycosylase, in addition to alleviating is also able to promote mutation induction by 5-formyldeoxyuridine in E.
    [Show full text]