DNA strand breaks produced by oxidative stress in mammalian cells exhibit 3′-phosphoglycolate termini

Bertoncini, Clélia Rejane Antônio; Meneghini, Rogério

doi:10.1093/nar/23.15.2995

Cited by 88 publications

(46 citation statements)

References 43 publications

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“…DNA hypomethylation may in turn be linked mechanistically to the observed increase in urinary oxo (8)dG and DNA strand breaks through increased accessibility of internucleosomal sites (56). Oxidative stress causes DNA damage by one or two interactive events: intracellular hydroxyl radical formation secondary to the reaction of H 2 O 2 with a DNA-bound metal ion and͞or oxidation-induced rise in cellular calcium transport that triggers Ca ϩ2 -dependent endonuclease activity and strand breakage (57,58). At the same time, nucleotide imbalance secondary to abnormal methionine metabolism promotes hepatocellular apoptosis, as described in our prior study of ethanolfed micropigs (16) and in rats fed folate-and methyl-deficient diets (15).…”

Section: Discussionmentioning

confidence: 99%

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Halsted

Villanueva

Devlin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

185

179

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Alcoholic liver disease is associated with abnormal hepatic methionine metabolism and folate deficiency. Because folate is integral to the methionine cycle, its deficiency could promote alcoholic liver disease by enhancing ethanol-induced perturbations of hepatic methionine metabolism and DNA damage. We grouped 24 juvenile micropigs to receive folate-sufficient (FS) or folate-depleted (FD) diets or the same diets containing 40% of energy as ethanol (FSE and FDE) for 14 wk, and the significance of differences among the groups was determined by ANOVA. Plasma homocysteine levels were increased in all experimental groups from 6 wk onward and were greatest in FDE. Ethanol feeding reduced liver methionine synthase activity, S-adenosylmethionine (SAM), and glutathione, and elevated plasma malondialdehyde (MDA) and alanine transaminase. Folate deficiency decreased liver folate levels and increased global DNA hypomethylation. Ethanol feeding and folate deficiency acted together to decrease the liver SAM͞S-adenosylhomocysteine (SAH) ratio and to increase liver SAH, DNA strand breaks, urinary 8-oxo-2 -deoxyguanosine [oxo(8)dG]͞mg of creatinine, plasma homocysteine, and aspartate transaminase by more than 8-fold. Liver SAM correlated positively with glutathione, which correlated negatively with plasma MDA and urinary oxo(8)dG. Liver SAM͞SAH correlated negatively with DNA strand breaks, which correlated with urinary oxo(8)dG. Livers from ethanol-fed animals showed increased centrilobular CYP2E1 and protein adducts with acetaldehyde and MDA. Steatohepatitis occurred in five of six pigs in FDE but not in the other groups. In summary, folate deficiency enhances perturbations in hepatic methionine metabolism and DNA damage while promoting alcoholic liver injury. F olate deficiency is among the most common nutritional abnormalities in chronic alcoholic patients, especially in those who have developed alcoholic liver injury (1-5). In addition to poor diet, folate deficiency in chronic alcoholism can be ascribed to decreased intestinal absorption and hepatic uptake, increased renal excretion, and increased oxidative cleavage of the folate molecule (6-12). Folate in its 5-methyltetrahydrofolate (5-MTHF) form is integral to methionine metabolism. Folate deficiency perturbs hepatic methionine metabolism (13,14), which is associated with DNA nucleotide imbalance and increased hepatocellular apoptosis in experimental animals fed folate-deficient (FD) diets or exposed to chronic ethanol (15,16).Hepatic methionine metabolism is regulated by the availability of dietary and endogenous folate that appears in the circulation as 5-MTHF and is the substrate with cofactor vitamin B 12 for the methionine synthase (MS) reaction that generates methionine from homocysteine (Hcy) (see supporting information, which is published on the PNAS web site, www.pnas.org). In the alternate salvage pathway for methionine synthesis, choline is the precursor of betaine, which is the substrate for betaine homocysteine methyltransferase (BHMT). The methionine adeno...

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Section: Discussionmentioning

confidence: 99%

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Halsted

Villanueva

Devlin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

185

179

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“…Because DNA can chelate Fe 2ϩ in several ways, DNA damage in vivo in prokaryotes (2) and eukaryotes (10,11), and in vitro (2,9) Hence, these oxidants appear to damage DNA only at lower H 2 O 2 concentrations; they are also scavenged by alcohols. The constant rate of damage observed with H 2 O 2 concentrations between 5 and 50 mM was defined to be due to type II oxidants.…”

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confidence: 99%

Sequence-specific DNA Cleavage by Fe2+-mediated Fenton Reactions Has Possible Biological Implications

Henle

Han

Tang

et al. 1999

Journal of Biological Chemistry

317

232

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Preferential cleavage sites have been determined for Fe 2؉ /H 2 O 2 -mediated oxidations of DNA. In 50 mM H 2 O 2 , preferential cleavages occurred at the nucleoside 5 to each of the dG moieties in the sequence RGGG, a sequence found in a majority of telomere repeats. Within a plasmid containing a (TTAGGG) 81 human telomere insert, 7-fold more strand breakage occurred in the restriction fragment with the insert than in a similar-sized control fragment. This result implies that telomeric DNA could protect coding DNA from oxidative damage and might also link oxidative damage and iron load to telomere shortening and aging. In micromolar H 2 O 2 , preferential cleavage occurred at the thymidine within the sequence RTGR, a sequence frequently found to be required in promoters for normal responses of many procaryotic and eucaryotic genes to iron or oxygen stress. Computer modeling of the interaction of Fe 2؉ with RTGR in B-DNA suggests that due to steric hindrance with the thymine methyl, Fe 2؉ associates in a specific manner with the thymine flipped out from the base stack so as to allow an octahedrally-oriented coordination of the Fe 2؉ with the three purine N 7 residues. Fe 2؉ -dependent changes in NMR spectra of duplex oligonucleotides containing ATGA versus those containing AUGA or A 5m CGA were consistent with this model.

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“…[3][4][5][6][7][8] However, there has been no direct experimental evidence to support such hypothesis. The surface reaction mode in our photoelectrochemical sensor provided a unique opportunity to investigate the role of DNA-associated metals in the Fenton reaction.…”

Section: Resultsmentioning

confidence: 99%

Photoelectrochemical Detection of Oxidative DNA Damage Induced by Fenton Reaction with Low Concentration and DNA-Associated Fe²⁺

2008

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The metal ion dependent decomposition of hydrogen peroxide, the so-called Fenton Reaction, yields hydroxyl radicals that can cause oxidative DNA damage both in Vitro and in ViVo. We have previously reported a photoelectrochemical sensor for the detection of oxidative DNA damage induced by an Fe 2+ -mediated Fenton Reaction, using a DNA intercalator as a photoelectrochemical signal reporter (Liang, M.; Guo, L.-H. EnViron. Sci. Technol. 2007, 41, 658). The intercalator binds less to the damaged DNA in the sensor film than the native form, resulting in a reduction in the measured photocurrent. In this report, some mechanistic aspects of the sensor were investigated. It was found that Fe 2+ alone (without the coexistence of H 2 O 2 ) suppressed the photocurrent of the intercalator bound to the DNA film in a pH-dependent manner. Similar pH dependence was observed for the potential of the tin oxide nanoparticle colloid used in the preparation of the semiconductor electrode, leading to the hypothesis that the metal ion binds to the surface oxide groups on the electrode and quenches the photoelectrochemical response. At pH 3, the quenching effect was reduced substantially to permit the detection of DNA damage by as low as 10 µM Fe 2+ and 40 µM H 2 O 2 , a concentration that is within the physiologically relevant range. It was also found that Fe 2+ ions associated with the DNA in the sensor film and participated in the DNA damage reaction, a mechanism that has been implicated in previous studies on metal carcinogenesis.

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DNA strand breaks produced by oxidative stress in mammalian cells exhibit 3′-phosphoglycolate termini

Cited by 88 publications

References 43 publications

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Sequence-specific DNA Cleavage by Fe2+-mediated Fenton Reactions Has Possible Biological Implications

Photoelectrochemical Detection of Oxidative DNA Damage Induced by Fenton Reaction with Low Concentration and DNA-Associated Fe²⁺

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DNA strand breaks produced by oxidative stress in mammalian cells exhibit 3′-phosphoglycolate termini

Cited by 88 publications

References 43 publications

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Sequence-specific DNA Cleavage by Fe2+-mediated Fenton Reactions Has Possible Biological Implications

Photoelectrochemical Detection of Oxidative DNA Damage Induced by Fenton Reaction with Low Concentration and DNA-Associated Fe2+

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Photoelectrochemical Detection of Oxidative DNA Damage Induced by Fenton Reaction with Low Concentration and DNA-Associated Fe²⁺