Excision Repair in Mammalian Cells *
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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. -
Mechanism and Regulation of DNA Damage Recognition in Nucleotide Excision Repair
Kusakabe et al. Genes and Environment (2019) 41:2 https://doi.org/10.1186/s41021-019-0119-6 REVIEW Open Access Mechanism and regulation of DNA damage recognition in nucleotide excision repair Masayuki Kusakabe1, Yuki Onishi1,2, Haruto Tada1,2, Fumika Kurihara1,2, Kanako Kusao1,3, Mari Furukawa1, Shigenori Iwai4, Masayuki Yokoi1,2,3, Wataru Sakai1,2,3 and Kaoru Sugasawa1,2,3* Abstract Nucleotide excision repair (NER) is a versatile DNA repair pathway, which can remove an extremely broad range of base lesions from the genome. In mammalian global genomic NER, the XPC protein complex initiates the repair reaction by recognizing sites of DNA damage, and this depends on detection of disrupted/destabilized base pairs within the DNA duplex. A model has been proposed that XPC first interacts with unpaired bases and then the XPD ATPase/helicase in concert with XPA verifies the presence of a relevant lesion by scanning a DNA strand in 5′-3′ direction. Such multi-step strategy for damage recognition would contribute to achieve both versatility and accuracy of the NER system at substantially high levels. In addition, recognition of ultraviolet light (UV)-induced DNA photolesions is facilitated by the UV-damaged DNA-binding protein complex (UV-DDB), which not only promotes recruitment of XPC to the damage sites, but also may contribute to remodeling of chromatin structures such that the DNA lesions gain access to XPC and the following repair proteins. Even in the absence of UV-DDB, however, certain types of histone modifications and/or chromatin remodeling could occur, which eventually enable XPC to find sites with DNA lesions. -
Role of Apurinic/Apyrimidinic Nucleases in the Regulation of Homologous Recombination in Myeloma: Mechanisms and Translational S
Kumar et al. Blood Cancer Journal (2018) 8:92 DOI 10.1038/s41408-018-0129-9 Blood Cancer Journal ARTICLE Open Access Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance Subodh Kumar1,2, Srikanth Talluri1,2, Jagannath Pal1,2,3,XiaoliYuan1,2, Renquan Lu1,2,PuruNanjappa1,2, Mehmet K. Samur1,4,NikhilC.Munshi1,2,4 and Masood A. Shammas1,2 Abstract We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We now demonstrate that base excision repair (BER) associated apurinic/apyrimidinic (AP) nucleases (APEX1 and APEX2) contribute to regulation of HR in MM cells. Transgenic as well as chemical inhibition of APEX1 and/or APEX2 inhibits HR activity in MM cells, whereas the overexpression of either nuclease in normal human cells, increases HR activity. Regulation of HR by AP nucleases could be attributed, at least in part, to their ability to regulate recombinase (RAD51) expression. We also show that both nucleases interact with major HR regulators and that APEX1 is involved in P73-mediated regulation of RAD51 expression in MM cells. Consistent with the role in HR, we also show that AP-knockdown or treatment with inhibitor of AP nuclease activity increases sensitivity of MM cells to melphalan and PARP inhibitor. Importantly, although inhibition 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; of AP nuclease activity increases cytotoxicity, it reduces genomic instability caused by melphalan. In summary, we show that APEX1 and APEX2, major BER proteins, also contribute to regulation of HR in MM. -
Loss of DNA Mismatch Repair Facilitates Reactivation of a Reporter
British Journal of Cancer (1999) 80(5/6), 699–704 © 1999 Cancer Research Campaign Article no. bjoc.1998.0412 Loss of DNA mismatch repair facilitates reactivation of a reporter plasmid damaged by cisplatin B Cenni1,†, H-K Kim1, GJ Bubley2, S Aebi1, D Fink1, BA Teicher3,*, SB Howell1 and RD Christen1 1Department of Medicine 0058, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0058, USA; 2Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA 02115, USA; 3Division of Cancer Pharmacology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA Summary In addition to recognizing and repairing mismatched bases in DNA, the mismatch repair (MMR) system also detects cisplatin DNA adducts and loss of MMR results in resistance to cisplatin. A comparison was made of the ability of MMR-proficient and -deficient cells to remove cisplatin adducts from their genome and to reactivate a transiently transfected plasmid that had previously been inactivated by cisplatin to express the firefly luciferase enzyme. MMR deficiency due to loss of hMLH1 function did not change the extent of platinum (Pt) accumulation or kinetics of removal from total cellular DNA. However, MMR-deficient cells, lacking either hMLH1 or hMSH2, generated twofold more luciferase activity from a cisplatin-damaged reporter plasmid than their MMR-proficient counterparts. Thus, detection of the cisplatin adducts by the MMR system reduced the efficiency of reactivation of the damaged luciferase gene compared to cells lacking this detector. The twofold reduction in reactivation efficiency was of the same order of magnitude as the difference in cisplatin sensitivity between the MMR-proficient and -deficient cells. -
DNA Repair with Its Consequences (E.G
Cell Science at a Glance 515 DNA repair with its consequences (e.g. tolerance and pathways each require a number of apoptosis) as well as direct correction of proteins. By contrast, O-alkylated bases, Oliver Fleck* and Olaf Nielsen* the damage by DNA repair mechanisms, such as O6-methylguanine can be Department of Genetics, Institute of Molecular which may require activation of repaired by the action of a single protein, Biology, University of Copenhagen, Øster checkpoint pathways. There are various O6-methylguanine-DNA Farimagsgade 2A, DK-1353 Copenhagen K, Denmark forms of DNA damage, such as base methyltransferase (MGMT). MGMT *Authors for correspondence (e-mail: modifications, strand breaks, crosslinks removes the alkyl group in a suicide fl[email protected]; [email protected]) and mismatches. There are also reaction by transfer to one of its cysteine numerous DNA repair pathways. Each residues. Photolyases are able to split Journal of Cell Science 117, 515-517 repair pathway is directed to specific Published by The Company of Biologists 2004 covalent bonds of pyrimidine dimers doi:10.1242/jcs.00952 types of damage, and a given type of produced by UV radiation. They bind to damage can be targeted by several a UV lesion in a light-independent Organisms are permanently exposed to pathways. Major DNA repair pathways process, but require light (350-450 nm) endogenous and exogenous agents that are mismatch repair (MMR), nucleotide as an energy source for repair. Another damage DNA. If not repaired, such excision repair (NER), base excision NER-independent pathway that can damage can result in mutations, diseases repair (BER), homologous recombi- remove UV-induced damage, UVER, is and cell death. -
DNA Replication, Repair and Recombination
DNA replication, repair and recombination Asst. Prof. Dr. Altijana Hromic-Jahjefendic SS2020 DNA Genetic material Eukaryotes: in nucleus Prokaryotes: as plasmid Mitosis Division and duplication of somatic cells Production of two identical daughter cells from a single parent cell 4 stages: Prophase: The chromatin condenses into chromosomes. Each chromosome has duplicated to tow sister chromatids. The nuclear envelope breaks down. Metaphase: The chromosomes align at the equatorial plate and are held by microtubules attached to the mitotic spindle and to part of the centromere Anaphase: Centromeres divide and sister chromatids separate and move to corresponding poles Telophase: Daughter chromosomes arrive at the poles and the microtubules disappear. The nuclear envelope reappears DNA replication & recombination Reproduction (Replication) of a DNA-double helix - semiconservative fashion demonstrated by Meselson & Stahl by using 15N-labeled ammonium chloride in the growth medium heavy nitrogen label was incorporated in the DNA of the bacteria shifted to normal 14N-medium giving rise to density band between the “heavy” and the “light” band in the 1st generation In the 2nd generation, in addition to the hybrid band a light band appears which contains only 14N- DNA Synthesis of a new DNA strand nucleoside triphosphates are selected ability to form Watson-Crick base pairs to the corresponding position in the template strand DNA replication occurs at replication forks For replication - two parental DNA-strands must separate from -
Incision by Uvrabc Excinuclease Is a Step in the Path to Mutagenesis By
Proc. Nati. Acad. Sci. USA Vol. 86, pp. 3982-3986, June 1989 Biochemistry Incision by UvrABC excinuclease is a step in the path to mutagenesis by psoralen crosslinks in Escherichia coli (plasmid mutagenesis/pSV2-gpt/homologous recombination/angelicin/deletions) FRANCES M. SLADEK*t, AGUSTIN MELIANt, AND PAUL HOWARD-FLANDERS§ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511 Communicated by Fred Sherman, February 21, 1989 (receivedfor review June 10, 1988) ABSTRACT 4,5',8-Trimethylpsoralen (psoralen) plus yield of SOS-dependent mutations (15, 16), which tend to be near UV light produces interstrand crosslinks and monoad- base-pair substitutions (17-19). ducts in DNA, both ofwhich are mutagenic. InEscherichia coil, The repair of crosslinks appears to occur by a sequential crosslinks are incised by UvrABC excinuclease, an event that excision-recombination mechanism (20, 21). In vitro studies can lead to homologous recombination and repair. To deter- show that crosslinked DNA is incised by the UvrABC exci- mine whether UvrABC incision of crosslinks is a step in the nuclease (22, 23) so that an 11-base oligonucleotide containing path to mutagenesis as well as repair, the effect of DNA the crosslink is left attached to an intact DNA strand (24). They homologous to a target gene on a plasmid was determined. also show that RecA-mediated strand exchange can proceed pSV2-gpt DNA was treated with psoralen and transformed into past the crosslinked oligonucleotide (25) and that a second a pair of hosts: one was gpt', the other was A(gpt-ac)5. The round of incision by UvrABC can release the psoralen moeity DNA was extracted and transformed into a tester strain from the DNA (25, 26). -
Distribution of DNA Repair-Related Ests in Sugarcane
Genetics and Molecular Biology, 24 (1-4), 141-146 (2001) Distribution of DNA repair-related ESTs in sugarcane W.C. Lima, R. Medina-Silva, R.S. Galhardo and C.F.M. Menck* Abstract DNA repair pathways are necessary to maintain the proper genomic stability and ensure the survival of the organism, protecting it against the damaging effects of endogenous and exogenous agents. In this work, we made an analysis of the expression patterns of DNA repair-related genes in sugarcane, by determining the EST (expressed sequence tags) distribution in the different cDNA libraries of the SUCEST transcriptome project. Three different pathways - photoreactivation, base excision repair and nucleotide excision repair - were investigated by employing known DNA repair proteins as probes to identify homologous ESTs in sugarcane, by means of computer similarity search. The results showed that DNA repair genes may have differential expressions in tissues, depending on the pathway studied. These in silico data provide important clues on the potential variation of gene expression, to be confirmed by direct biochemical analysis. INTRODUCTION (The Arabidopsis Genome Initiative, 2000), have provided huge amounts of data that still need to be processed, in or- The genome of all living beings is constantly subject der to enable us to understand the physiological mecha- to damage generated by exogenous and endogenous fac- nisms of these organisms. This is the case of the DNA tors, reducing DNA stability and leading to an increase of repair pathways. Although repair and damage tolerance mutagenesis, cancer, cell death, senescence and other dele- mechanisms have been well described in bacteria, yeast, terious effects to organisms (de Laat et al., 1999). -
Redox Regulation of DNA Repair: Implications for Human Health and Cancer Therapeutic Development
ANTIOXIDANTS & REDOX SIGNALING Volume 12, Number 11, 2010 C OMPREHENSIVE INVITED REVIEW © Mary Ann Liebert, Inc. DOI: 10.1089/ ars.2009.2698 Redox Regulation of DNA Repair: Implications for Human Health and Cancer Therapeutic Development 2 2 Meihua Luo~ Hongzhen He, Mark R. Ke l ley ~ -3 and Millie M. Georgiadis .4 Abstract Red.ox reactions are known to regulate many important cellular processes. In this revievv, v.re focus on the role of redox regulation in DNA repair both in direct regulation of specific DNA repair proteins as well as indirect transcriptional regulation. A key player in the redox regulation of DNA repair is the base excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APEl) in its role as a redox factor. APEl is reduced by the general redox factor thioredoxin, and in turn reduces several important transcription factors that regulate expression of DNA repair proteins. Finally, we consider the potential for chemotherapeutic development through the modulation of APEl's redox activity and its impact on DNA repair. Antioxid. Redox Signal. 12, 1247-1269. l. Introduction 1248 II. DNA-Repair Pathways 1248 A. Mammalian d irect repair: 0 6-alkylguanine-DNA methyltransferase or 0 6-methylguanine-DNA methyltransferase 1249 B. Base-excision repair 1249 C. Nucleotide-excision repair 1249 D. Mismatch repair 1250 E. Nonhomologous DNA end-joining and homologous recombiJ.1ation 1250 ITT. General Redox Systems 1251 A. The thioredoxin system 1251 B. The glutaredoxin/glutathione system 1252 C. l~oles of general redox systems 1252 N. The Redox Activity of APEl 1252 A. Evolution of the redox function of APEl 1252 B. -
Dnase I Footprint of ABC Excinuclease”
THE JOURNALOF BIOLOGICAL CHEMISTRY Vol. 262, No. 27, Issue of September 25, pp. 13180-13187,1987 0 1987 by The American Societyfor Biochemistry and Molecular Biology, Inc. Printed in U.S.A. DNase I Footprint of ABC Excinuclease” (Received for publication, April 3, 1987) Bennett Van HoutenSg,Howard Gamperll((**,Aziz SancarS, and JohnE. HearstllJJ$$ From the $Department of Biochemistry, University ofNorth Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27514, the TDepartment of Chemistry, University of California, Berkeley, California 94720, and the ((Divisionof Chemical Biodynamics, Lawrence Berkeley Laboratory, Berkeley, California 94720 The incision and excision steps of nucleotide excision In Escherichia coli, the initial steps of nucleotide excision repair in Escherichia coli are mediated by ABC exci- repair are mediated by the enzyme ABC excision nuclease nuclease, a multisubunit enzyme composed of three (ABC excinuclease) which is composed of threeproteins, proteins, UvrA, UvrB, and UvrC. To determine the UvrA (Mr= 103,874), UvrB (M, = 76,118), and UvrC (M, = DNA contact sites and the binding affinity ofABC 66,038) (Husain et al., 1986; Arikan et al., 1986; Backendorf excinuclease for damaged DNA, it is necessary to en- et al., 1986; Sancar, G. et al., 1984). These subunits function gineer a DNA fragment uniquely modified at one nu- cleotide. We have recently reported the constructionof in a concerted manner to hydrolyze the 8th phosphodiester a 40 base pair (bp) DNA fragment containing a psora- bond 5’ and the 4th or 5th phosphodiester bond 3‘ to a len adduct at a central TpA sequence (Van Houten, B., modified nucleotide(s). -
DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces Cerevisiae
YEASTBOOK GENOME ORGANIZATION & INTEGRITY DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae Serge Boiteux* and Sue Jinks-Robertson†,1 *Centre National de la Recherche Scientifique UPR4301 Centre de Biophysique Moléculaire, 45071 Orléans cedex 02, France, and yDepartment of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710 ABSTRACT DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mech- anisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. -
Lecture 9.Pdf
Lecture-9 M.Sc 2nd Semester (Environmental Microbiology) Paper EM-202: Microbial physiology and adaptation Unit IV: SOS Inducible Repair Mechanism Against UV Induced Damage The SOS Response • The SOS response is the term used to describe changes in gene expression in E. coli in other bacteria in response to extensive DNA damage. The prokaryotic SOS system is regulated by two main protien i.e. Lex A and Rec A. •Despite having multiple repair system, sometimes the damage to an organism’s DNA is so great that the normal repair mechanisms just described cannot repair all the damage. As a result, DNA synthesis stops completely. In such situations, a global control network called the SOS response is activated. •The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the Spirochetes. •The SOS response, like recombination repair, is dependent on the activity of the RecA and Lex A protein . •. The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled replication fork or double-strand breaks, which are processed by DNA helicase to separate the two DNA strands. In the initiation step, RecA protein binds to ssDNA in an ATP hydrolysis driven reaction creating RecA–ssDNA filaments. •RecA binds to single or double stranded DNA breaks and gaps generated by cessation of DNA synthesis. RecA binding initiates recombination repair. •RecA–ssDNA filaments activate LexA auto protease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. •The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.