DNA strand scission by enzymically generated oxygen radicals

Brawn, Karen; Fridovich, Irwin

doi:10.1016/0003-9861(81)90108-9

Cited by 412 publications

(163 citation statements)

References 49 publications

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“…Hyperbaric oxygen induces mutations in bacteria [31] and chromosomal aberrations in eukaryotic cells [32,33], probably because the amount of reactive oxygen produced by cellular metabolism in this situation is increased [34]. Indeed, O~ and H202 mutagenize bacteria and induce DNA breaks and chromosomal aberrations [35,36]. Characteristic DNA lesions are single-and double-strand breaks, apurinic and apyrimidinic sites, and products of the 5,6-dihydroxydihydrothymine type.…”

Section: Oxidative Damage To Dna and Its Relationship To Cancer And Amentioning

confidence: 99%

Do mitochondrial DNA fragments promote cancer and aging?

Richter

1988

FEBS Letters

211

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Reactive oxygen species are important in carcinogenesis, diseases, and aging, probably through oxidative damage of DNA. Our understanding of this relationship at the molecular level is very sketchy. It has recently been found that in mitochondria oxidative DNA damage is particularly high and may not be repaired efficiently. I propose that oxidatively generated DNA fragments escape from mitochondria and become integrated into the nuclear genome. This may transform cells to a cancerous state. Time‐dependent nuclear accumulation of mitochondrial DNA fragments may progressively change the nuclear information content and thereby cause aging. This proposal can be tested experimentally.

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Section: Oxidative Damage To Dna and Its Relationship To Cancer And Amentioning

confidence: 99%

Do mitochondrial DNA fragments promote cancer and aging?

Richter

1988

FEBS Letters

211

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“…However, it can slowly oxidize the reduced flavins of many redox enzymes, thereby generating a mixture of superoxide (O 2 . ) and hydrogen peroxide (H 2 O 2 ) (1-3 (8,9). Oxidative DNA damage is therefore ascribed to a fourth oxygen species, the hydroxyl radical (HO ⅐ ).…”

mentioning

confidence: 99%

“…That reductant has not been identified. Superoxide itself is capable of reducing free iron and functions in that capacity in some in vitro Fenton systems (8,9,18). However, the intracellular concentration of superoxide is so low (ϳ10 Ϫ10 M) (19,20), and its reduction of bound iron so slow (ϳ10 5 M Ϫ1 s Ϫ1 ) (21), that the predicted half-time for this reaction in vivo is Ͼ10 h, far too long to be physiologically relevant.…”

mentioning

confidence: 99%

Reduced Flavins Promote Oxidative DNA Damage in Non-respiringEscherichia coli by Delivering Electrons to Intracellular Free Iron

Woodmansee

Imlay

2002

Journal of Biological Chemistry

131

163

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When cells are exposed to external H 2 O 2 , the H 2 O 2 rapidly diffuses inside and oxidizes ferrous iron, thereby forming hydroxyl radicals that damage DNA. Thus the process of oxidative DNA damage requires only H 2 O 2 , free iron, and an as-yet unidentified electron donor that reduces ferric iron to the ferrous state. Previous work showed that H 2 O 2 kills Escherichia coli especially rapidly when respiration is inhibited either by cyanide or by genetic defects in respiratory enzymes. In this study we established that these respiratory blocks accelerate the rate of DNA damage. The respiratory blocks did not substantially affect the amounts of intracellular free iron or H 2 O 2 , indicating that that they accelerated damage because they increased the availability of the electron donor. The goal of this work was to identify that donor. As expected, the respiratory inhibitors caused a large increase in the amount of intracellular NADH. However, NADH itself was a poor reductant of free iron in vitro. This suggests that in non-respiring cells electrons are transferred from NADH to another carrier that directly reduces the iron. Genetic manipulations of the amounts of intracellular glutathione, NADPH, ␣-ketoacids, ferredoxin, and thioredoxin indicated that none of these was the direct electron donor. However, cells were protected from cyanide-stimulated DNA damage if they lacked flavin reductase, an enzyme that transfers electrons from NADH to free FAD. The K m value of this enzyme for NADH is much higher than the usual intracellular NADH concentration, which explains why its flux increased when NADH levels rose during respiratory inhibition. Flavins that were reduced by purified flavin reductase rapidly transferred electrons to free iron and drove a DNA-damaging Fenton system in vitro. Thus the rate of oxidative DNA damage can be limited by the rate at which electron donors reduce free iron, and reduced flavins become the predominant donors in E. coli when respiration is blocked. It remains unclear whether flavins or other reductants drive Fenton chemistry in respiring cells.

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“…They ware suffering from cancer of female genital tract e.g., vagina, cervix & ovary (n = 7 ); breast cancer (n= 4); oral cancer (n= 8); laryngeal cancer (n= 4) ahd miscellaneous (n= 7) Figure 1. Binding of antibodies from the sera of larynx and oral cancer patients [1][2][3][4][5][6][7][8][9][10][11][12] to native (-I"1.) and ROS-modifled (-II-) DNA.…”

Section: ~176 I Detection Of Anti-ros-dna Antibodies In Cancer Patientsmentioning

confidence: 99%

“…Exposure of DNA to superoxide generating systems causes extensive strand breakage and degradation of deoxyribose (1), probably due to formation of hydroxyl radicals. Oxygen free radicals, especially hydroxyl radicals generated during cellular metabolism, have been known to cause DNA damage and their relevance in carcinogenesis is well documented (2-4).…”

Section: Introductionmentioning

confidence: 99%