Oxidation of DNA bases, deoxyribonucleosides and homopolymers by peroxyl radicals

Simandan, Tiberiu; Sun, Jing; Dix, Thomas A.

doi:10.1042/bj3350233

Cited by 64 publications

(51 citation statements)

References 47 publications

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“…Similar N-hydroxylated-compound-detoxification systems have been identified in organisms as diverse as humans (67) and green algae (68). Oxidative radicals promote generation of hydroxylated nucleobases (69). Knockdown of mitochondrial amidoxime reducing component 2 sensitizes HeLa cells to aminopurine (70), indicating that HeLa cells constitutively express machinery to cope with hydroxylated aminopurines.…”

Section: Discussionmentioning

confidence: 99%

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

et al. 2016

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cChlamydia trachomatis can enter a viable but nonculturable state in vitro termed persistence. A common feature of C. trachomatis persistence models is that reticulate bodies fail to divide and make few infectious progeny until the persistence-inducing stressor is removed. One model of persistence that has relevance to human disease involves tryptophan limitation mediated by the host enzyme indoleamine 2,3-dioxygenase, which converts L-tryptophan to N-formylkynurenine. Genital C. trachomatis strains can counter tryptophan limitation because they encode a tryptophan-synthesizing enzyme. Tryptophan synthase is the only enzyme that has been confirmed to play a role in interferon gamma (IFN-␥)-induced persistence, although profound changes in chlamydial physiology and gene expression occur in the presence of persistence-inducing stressors. Thus, we screened a population of mutagenized C. trachomatis strains for mutants that failed to reactivate from IFN-␥-induced persistence. Six mutants were identified, and the mutations linked to the persistence phenotype in three of these were successfully mapped. One mutant had a missense mutation in tryptophan synthase; however, this mutant behaved differently from previously described synthase null mutants. Two hypothetical genes of unknown function, ctl0225 and ctl0694, were also identified and may be involved in amino acid transport and DNA damage repair, respectively. Our results indicate that C. trachomatis utilizes functionally diverse genes to mediate survival during and reactivation from persistence in HeLa cells. Chlamydia trachomatis has a characteristic biphasic developmental cycle in cell culture (1). The two dominant chlamydial forms are elementary bodies (EBs) and reticulate bodies (RBs) (1). EBs represent the infectious, nonreplicative form capable of invading host cells (1). Following entry, EBs differentiate into RBs that replicate inside parasitophorous vacuoles termed inclusions (1). Maturing RBs then redifferentiate back to EBs and exit the host cell via lysis or extrusion (2). Morphologically aberrant RBs have been observed in clinical specimens (3). This abnormal developmental cycle can be recapitulated in a laboratory setting by exposing C. trachomatis to various stressors such as host cytokines (4-6), excess amino acids (7), iron deficiency (8, 9), virus coinfections (10), and antibiotics (11, 12) (reviewed in reference 13). Under these conditions, normal C. trachomatis RBs can transition into persistent forms that do not divide, are enlarged, and have aberrant morphology (13). Upon removal of the persistence-inducing stressor, RBs transition back into normal RBs and continue normal development (13). Aberrant RB morphology is a shared feature of multiple C. trachomatis persistence models and may reflect activation of a common stress response program (13). Thus, characterizing how C. trachomatis enters, survives, and reactivates from persistence could reveal new insights into chlamydial pathogenesis.The Th1 cytokine interferon gamma (IFN-␥) can induce dif...

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Section: Discussionmentioning

confidence: 99%

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

et al. 2016

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“…Interestingly, HAP may also be produced by DNA oxidation resulting from oxidative stress. Experiments exposing DNA and DNA bases to peroxyl radical (ROOϪ), a major intracellular oxidant and oxidative stress product, showed HAP to be the major product (55).…”

Section: Discussionmentioning

confidence: 99%

Hypersensitivity of Escherichia coli Δ ( uvrB-bio ) Mutants to 6-Hydroxylaminopurine and Other Base Analogs Is Due to a Defect in Molybdenum Cofactor Biosynthesis

et al. 2000

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We have shown previously that Escherichia coli and Salmonella enterica serovar Typhimurium strains carrying a deletion of the uvrB-bio region are hypersensitive to the mutagenic and toxic action of 6-hydroxylaminopurine (HAP) and related base analogs. This sensitivity is not due to the uvrB excision repair defect associated with this deletion because a uvrB point mutation or a uvrA deficiency does not cause hypersensitivity. In the present work, we have investigated which gene(s) within the deleted region may be responsible for this effect. Using independent approaches, we isolated both a point mutation and a transposon insertion in the moeA gene, which is located in the region covered by the deletion, that conferred HAP sensitivity equal to that conferred by the uvrB-bio deletion. The moeAB operon provides one of a large number of genes responsible for biosynthesis of the molybdenum cofactor. Defects in other genes in the same pathway, such as moa or mod, also lead to the same HAP-hypersensitive phenotype. We propose that the molybdenum cofactor is required as a cofactor for an as yet unidentified enzyme (or enzymes) that acts to inactivate HAP and other related compounds.The biological effects of many mutagenic agents are due to DNA base modifications, both in the DNA and the DNA precursor pool. A group of mutagens containing a preformed modified base, often referred to as base analogs (14), have received increasing attention recently. For example, 8-oxoguanine, in the form of 8-oxo-dGTP or 8-oxo-GTP, is a spontaneously arising guanine oxidation product that contributes substantially to the infidelity of DNA replication (13,35,37) or transcription (58). Specialized systems protecting the cell against 8-oxoguanine have been found in organisms from bacteria to humans (for reviews, see references 13 and 37), including the MutT enzyme, which is capable of hydrolyzing 8-oxodGTP, an activity referred to as pool sanitizing (2,35). Other examples of mutagenic precursor pool contaminants are 5-hydroxy-dCTP (12) and 2-hydroxy-dATP (15), both oxidative stress products. The human MutT homolog hMTH1 has strong activity towards 2-hydroxy-dATP, suggesting that it, in addition to 8-oxo-GTP, could be an important threat if not actively removed (15). In addition, base analogs can be useful tools for probing the mechanisms of mutation avoidance during DNA replication, including base-base discrimination by DNA polymerases (51, 54).An important group of base analogs are the N-hydroxy derivatives of adenine and cytidine (see reference 27 for a review). For example, 6-hydroxylaminopurine (N-6-hydroxyadenine) (HAP) and 2-amino-6-hydroxylaminopurine (AHAP) are very powerful mutagens in phage, bacteria, yeast, and eukaryotic cells (42, 43), and they have been termed universal mutagens (42). These adenine derivatives are active when provided as bases or, in some organisms, nucleosides, as they are apparently converted efficiently into the corresponding deoxynucleoside triphosphates (dNTPs), which are then incorporated into DNA by DNA po...

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“…Free radicals may be generated when these metal ions acquire electrons from donor species, such as oxygen, to form highly reactive oxygen radicals, although a number of possibilities exist for potential oxygen radical species, for example, the superoxide anion and the hydroxyl radical. Substantial evidence exists for the association between generation of reactive oxygen species and various forms of toxicity [35][36][37], including those induced by metal compounds [38,39], the variation in acute toxicity for the metals under consideration may be due to their ability to produce reactive oxygen species. In addition to direct combination with molecular oxygen, the possibility of hydroxyl radical generation [40] also occurs when the metal ion reacts with water, according to the following equation:…”

Section: Resultsmentioning

confidence: 99%

Metal toxicity in two rodent species and redox potential: Evaluation of quantitative structure—activity relationships

Lewis

Dobrota

Taylor

et al. 1999

Enviro Toxic and Chemistry

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A quantitative structure-activity relationship study of acute toxicity in the mouse and rat is described for the soluble salts of a relatively large number of metals (between 25 and 30 in total). Electrode potential is the major determinant of acute metal toxicity (R = 0.85 and 0.86) for an intraperitoneal dose in the mouse, whereas the addition of ionic radius and polarizability enables the inclusion of notable outliers in the original expression, such as beryllium and barium, thus giving a good correlation (R = 0.87) with toxicity for 27 metal compounds. These findings are rationalized on the basis of relative ease of ionization, electron affinity, and transport factors of the metals and their ions, thus being consistent with the hard and soft acids and bases properties of metals and their biological reactivities.

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Oxidation of DNA bases, deoxyribonucleosides and homopolymers by peroxyl radicals

Cited by 64 publications

References 47 publications

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

Beyond Tryptophan Synthase: Identification of Genes That Contribute to Chlamydia trachomatis Survival during Gamma Interferon-Induced Persistence and Reactivation

Hypersensitivity of Escherichia coli Δ ( uvrB-bio ) Mutants to 6-Hydroxylaminopurine and Other Base Analogs Is Due to a Defect in Molybdenum Cofactor Biosynthesis

Metal toxicity in two rodent species and redox potential: Evaluation of quantitative structure—activity relationships

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