scholarly journals Nitric Oxide-Induced Homologous Recombination in Escherichia coli Is Promoted by DNA Glycosylases

2002 ◽  
Vol 184 (13) ◽  
pp. 3501-3507 ◽  
Author(s):  
Erik J. Spek ◽  
Laurel N. Vuong ◽  
Tetsuya Matsuguchi ◽  
Martin G. Marinus ◽  
Bevin P. Engelward
Keyword(s):  
Nitric Oxide ◽  
Homologous Recombination ◽  
Excision Repair ◽  
Underlying Mechanism ◽  
Double Strand Breaks ◽  
Dna Glycosylases ◽  
Base Damage ◽  
Ap Endonuclease ◽  
Strand Breaks ◽  
Base Excision

ABSTRACT Nitric oxide (NO.) is involved in neurotransmission, inflammation, and many other biological processes. Exposure of cells to NO. leads to DNA damage, including formation of deaminated and oxidized bases. Apurinic/apyrimidinic (AP) endonuclease-deficient cells are sensitive to NO. toxicity, which indicates that base excision repair (BER) intermediates are being generated. Here, we show that AP endonuclease-deficient cells can be protected from NO. toxicity by inactivation of the uracil (Ung) or formamidopyrimidine (Fpg) DNA glycosylases but not by inactivation of a 3-methyladenine (AlkA) DNA glycosylase. These results suggest that Ung and Fpg remove nontoxic NO.-induced base damage to create BER intermediates that are toxic if they are not processed by AP endonucleases. Our next goal was to learn how Ung and Fpg affect susceptibility to homologous recombination. The RecBCD complex is critical for repair of double-strand breaks via homologous recombination. When both Ung and Fpg were inactivated in recBCD cells, survival was significantly enhanced. We infer that both Ung and Fpg create substrates for recombinational repair, which is consistent with the observation that disrupting ung and fpg suppressed NO.-induced recombination. Taken together, a picture emerges in which the action of DNA glycosylases on NO.-induced base damage results in the accumulation of BER intermediates, which in turn can induce homologous recombination. These studies shed light on the underlying mechanism of NO.-induced homologous recombination.

scholarly journals DNA DAMAGE AND REPAIR IN EUKARYOTIC CELLS

Genetics ◽  
1974 ◽  
Vol 78 (1) ◽  
pp. 139-148
Author(s):  
R B Painter
Keyword(s):  
Ionizing Radiation ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Single Strand ◽  
Premature Aging ◽  
Cross Linking ◽  
Base Damage ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Post Replication Repair

ABSTRACT Damage in DNA after irradiation can be classified into five kinds: base damage, single-strand breaks, double-strand breaks, DNA-DNA cross-linking, and DNA-protein cross-linking. Of these, repair of base damage is the best understood. In eukaryotes, at least three repair systems are known that can deal with base damage: photoreactivation, excision repair, and post-replication repair. Photoreactivation is specific for UV-induced damage and occurs widely throughout the biosphere, although it seems to be absent from placental mammals. Excision repair is present in prokaryotes and in animals but does not seem to be present in plants. Post-replication repair is poorly understood. Recent reports indicate that growing points in mammalian DNA simply skip past UV-induced lesions, leaving gaps in newly made DNA that are subsequently filled in by de novo synthesis. Evidence that this concept is oversimplified or incorrect is presented.—Single-strand breaks are induced by ionizing radiation but most cells can rapidly repair most or all of them, even after supralethal doses. The chemistry of the fragments formed when breaks are induced by ionizing radiation is complex and poorly understood. Therefore, the intermediate steps in the repair of single-strand breaks are unknown. Double-strand breaks and the two kinds of cross-linking have been studied very little and almost nothing is known about their mechanisms for repair.—The role of mammalian DNA repair in mutations is not known. Although there is evidence that defective repair can lead to cancer and/or premature aging in humans, the relationship between the molecular defects and the diseased state remains obscure.

scholarly journals Nonhomologous end joining of complex DNA double-strand breaks with proximal thymine glycol and interplay with base excision repair

DNA Repair ◽  
2016 ◽  
Vol 41 ◽  
pp. 16-26 ◽  
Author(s):  
Mohammed Almohaini ◽  
Sri Lakshmi Chalasani ◽  
Duaa Bafail ◽  
Konstantin Akopiants ◽  
Tong Zhou ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Thymine Glycol ◽  
Base Excision

scholarly journals Inhibition of DNA Repair in Combination with Temozolomide or Dianhydrogalactiol Overcomes Temozolomide-Resistant Glioma Cells

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2570
Author(s):  
Shigeo Ohba ◽  
Kei Yamashiro ◽  
Yuichi Hirose
Keyword(s):  
Homologous Recombination ◽  
Mismatch Repair ◽  
Dna Methyltransferase ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Resistance Mechanisms ◽  
Double Strand Breaks ◽  
Repair System ◽  
Strand Breaks ◽  
Resistant Cells

Resistance to temozolomide and intratumoral heterogeneity contribute to the poor prognosis of glioma. The mechanisms of temozolomide resistance can vary within a heterogeneous tumor. Temozolomide adds a methyl group to DNA. The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to a futile DNA mismatch repair cycle, formation of double-strand breaks, and eventual cell death when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The study aim was to elucidate temozolomide resistance mechanisms and identify methods to overcome temozolomide resistance in glioma. Several temozolomide-resistant clones were analyzed. Increased homologous recombination and mismatch repair system deficiencies contributed to temozolomide resistance. Inhibition of homologous recombination resensitized resistant cells with high homologous recombination efficiency. For the mismatch repair-deficient cells, inhibition of BER by PARP inhibitor potentiated temozolomide-induced cytotoxicity. Dianhydrogalactiol is a bifunctional DNA-targeting agent that forms N7-alkylguanine and inter-strand DNA crosslinks. Dianhydrogalactiol reduced the proliferation of cells independent of MGMT and mismatch repair, inducing DNA double-strand breaks and apoptosis in temozolomide-resistant cells. Further, inhibition of chk1 or homologous recombination enhanced dianhydrogalactiol-induced cytotoxicity in the cells. Selecting treatments most appropriate to the types of resistance mechanisms can potentially improve the prognosis of glioma.

scholarly journals Molecular Mechanisms of H. pylori Induced DNA Double-Strand Breaks

2018 ◽  
Author(s):  
Dawit Kidane
Keyword(s):  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Current Knowledge ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Base Excision ◽  
H Pylori

Infections contribute to carcinogenesis through inflammation-related mechanisms. It is well established that H. pylori infection is an etiological factor in gastric carcinogenesis. However, the mechanism through which H. pylori infection contributes to the development of gastric cancer has not been fully elucidated. H. pylori-associated chronic inflammation is linked to genomic instability via reactive oxygen and nitrogen species (RONS). In this article, we summarize the current knowledge of H. pylori-induced double strand breaks (DSBs). Further, we will provide mechanistic insight into how processing of oxidative DNA damage via base excision repair (BER) leads to double strand breaks (DSBs). We review the recent progress how H. pylori infection triggers NF-kB /iNOS versus NF-kB/nucleotide excision repair (NER) axis mediated DSBs to drive genomic instability. Taken together, this review discusses current findings related to DSBs and their implications for the mechanisms of DSB repair.

scholarly journals Evolutionary Origins of DNA Repair Pathways: Role of Oxygen Catastrophe in the Emergence of DNA Glycosylases

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1591
Author(s):  
Paulina Prorok ◽  
Inga R. Grin ◽  
Bakhyt T. Matkarimov ◽  
Alexander A. Ishchenko ◽  
Jacques Laval ◽  
...  
Keyword(s):  
Excision Repair ◽  
Dna Lesions ◽  
Dna Glycosylases ◽  
Cytosine Deamination ◽  
Ap Endonuclease ◽  
Evolutionary Origins ◽  
Universal Common Ancestor ◽  
Repair Mechanisms ◽  
Base Excision ◽  
Free Environment

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 major factor affecting LUCA’s genome integrity. Cosmic radiation due to Earth’s weak magnetic field and alkylating metabolic radicals added to these threats. Here, we propose that ancient forms of life had only two distinct repair mechanisms: versatile apurinic/apyrimidinic (AP) endonucleases to cope with both AP sites and deaminated residues, and enzymes catalyzing the direct reversal of UV and alkylation damage. The absence of uracil–DNA N-glycosylases in some Archaea, together with the presence of an AP endonuclease, which can cleave uracil-containing DNA, suggests that the AP endonuclease-initiated nucleotide incision repair (NIR) pathway evolved independently from DNA glycosylase-mediated base excision repair. NIR may be a relic that appeared in an early thermophilic ancestor to counteract spontaneous DNA damage. We hypothesize that a rise in the oxygen level in the Earth’s atmosphere ~2 Ga triggered the narrow specialization of AP endonucleases and DNA glycosylases to cope efficiently with a widened array of oxidative base damage and complex DNA lesions.

scholarly journals MBD4 Facilitates Immunoglobulin Class Switch Recombination

2016 ◽  
Vol 37 (2) ◽  
Author(s):  
Fernando Grigera ◽  
Robert Wuerffel ◽  
Amy L. Kenter
Keyword(s):  
Excision Repair ◽  
Cytidine Deaminase ◽  
Ectopic Expression ◽  
Class Switch Recombination ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Class Switch ◽  
Activation Induced Cytidine Deaminase ◽  
Base Excision

ABSTRACT Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double-strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation-induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme methyl-CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when Mbd4 exons 6 to 8 are deleted in a switching B cell line, DSB formation is severely reduced and CSR frequency is impaired. Impaired CSR can be rescued by ectopic expression of Mbd4. Mbd4 deficiency yields a deficit in DNA end processing similar to that found in MutS homologue 2 (Msh2)- and Mlh1-deficient B cells. We demonstrate that microhomology-rich S-S junctions are enriched in cells in which Mbd4 is deleted. Our studies suggest that Mbd4 is a component of MMR-directed DNA end processing.

Antimetabolite Radiosensitizers

2007 ◽  
Vol 25 (26) ◽  
pp. 4043-4050 ◽  
Author(s):  
Donna S. Shewach ◽  
Theodore S. Lawrence
Keyword(s):  
Excision Repair ◽  
Growth Factor Receptor ◽  
Double Strand Breaks ◽  
Egfr Inhibitors ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Solid Malignancies ◽  
Target Dna ◽  
Epidermal Growth ◽  
Base Excision

Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and neck. Fluorouracil (FU) and hydroxyurea have been widely used clinically during the last four decades, and promising results have been observed more recently with gemcitabine. Although the antimetabolites all target DNA replication, they differ with respect to the mechanisms by which they produce radiosensitization. The antimetabolite radiosensitizers may inhibit thymidylate synthase (TS) or ribonucleotide reductase, and the nucleoside/nucleobase analogs can be incorporated into DNA. Radiosensitization can result from chemotherapy-induced increase in DNA double-strand breaks or inhibition of their repair. Studies of repair pathways involved in radiosensitization with antimetabolites implicate base excision repair with the TS inhibitors, homologous recombination with gemcitabine, and mismatch repair with FU and gemcitabine. Gemcitabine can also stimulate epidermal growth factor receptor (EGFR) phosphorylation; inhibiting this effect with EGFR inhibitors can potentiate cytotoxicity and radiosensitization. Additional work is necessary to determine more precisely the processes by which antimetabolites act as radiation sensitizers and to define the optimal sequencing of these agents with EGFR inhibitors to provide better guidance for clinical protocols combining these drugs with radiotherapy.

scholarly journals OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1483
Author(s):  
Bishoy M. F. Hanna ◽  
Thomas Helleday ◽  
Oliver Mortusewicz
Keyword(s):  
Excision Repair ◽  
Double Strand Breaks ◽  
Dna Glycosylase ◽  
Chromatin Binding ◽  
Dna Double Strand Breaks ◽  
Chromatin Dynamics ◽  
Strand Breaks ◽  
Pathological Conditions ◽  
Base Excision

8-oxoguanine DNA glycosylase (OGG1) is the main DNA glycosylase responsible for the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex DNA to initiate base excision repair. This glycosylase activity is relevant in many pathological conditions including cancer, inflammation, and neurodegenerative diseases. To have a better understanding of the role of OGG1, we previously reported TH5487, a potent active site inhibitor of OGG1. Here, we further investigate the consequences of inhibiting OGG1 with TH5487. TH5487 treatment induces accumulation of genomic 8-oxoG lesions. Furthermore, it impairs the chromatin binding of OGG1 and results in lower recruitment of OGG1 to regions of DNA damage. Inhibiting OGG1 with TH5487 interferes with OGG1′s incision activity, resulting in fewer DNA double-strand breaks in cells exposed to oxidative stress. This study validates TH5487 as a potent OGG1 inhibitor that prevents the repair of 8-oxoG and alters OGG1–chromatin dynamics and OGG1′s recruitment kinetics.

scholarly journals The Transition of Closely Opposed Lesions to Double-Strand Breaks during Long-Patch Base Excision Repair Is Prevented by the Coordinated Action of DNA Polymerase δ and Rad27/Fen1

2008 ◽  
Vol 29 (5) ◽  
pp. 1212-1221 ◽  
Author(s):  
Wenjian Ma ◽  
Vijayalakshmi Panduri ◽  
Joan F. Sterling ◽  
Bennett Van Houten ◽  
Dmitry A. Gordenin ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Single Strand ◽  
S1 Nuclease ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Dna Polymerase Δ ◽  
Base Excision

ABSTRACT DNA double-strand breaks can result from closely opposed breaks induced directly in complementary strands. Alternatively, double-strand breaks could be generated during repair of clustered damage, where the repair of closely opposed lesions has to be well coordinated. Using single and multiple mutants of Saccharomyces cerevisiae (budding yeast) that impede the interaction of DNA polymerase δ and the 5′-flap endonuclease Rad27/Fen1 with the PCNA sliding clamp, we show that the lack of coordination between these components during long-patch base excision repair of alkylation damage can result in many double-strand breaks within the chromosomes of nondividing haploid cells. This contrasts with the efficient repair of nonclustered methyl methanesulfonate-induced lesions, as measured by quantitative PCR and S1 nuclease cleavage of single-strand break sites. We conclude that closely opposed single-strand lesions are a unique threat to the genome and that repair of closely opposed strand damage requires greater spatial and temporal coordination between the participating proteins than does widely spaced damage in order to prevent the development of double-strand breaks.

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