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HO* radicals induce an unexpected high proportion of tandem base lesions refractory to repair by DNA glycosylases.

ABSTRACT: Reaction of HO(*) radicals with double-stranded calf thymus DNA produces high levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and, to a minor extent, 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodAdo). Formation of the hydroxylated purine lesions is explained by addition of HO(*) to the C8 position of the purine moiety. It has been reported that tandem lesions containing a formylamine residue neighboring 8-oxodGuo could be produced through addition of a transiently generated pyrimidine peroxyl radical onto the C8 of an adjacent purine base. Formation of such tandem lesions accounted for approximately 10% of the total 8-oxodGuo. In the present work we show that addition of HO(*) onto the C8 of purine accounts for only approximately 5% of the generated 8-oxodGuo. About 50% of the 8-hydroxylated purine lesions, including 8-oxodGuo and 8-oxodAdo, are involved in tandem damage and are produced by peroxyl addition onto the C8 of a vicinal purine base. In addition, the remaining 45% of the 8-oxodGuo are produced by an electron transfer reaction, providing an explanation for the higher yield of formation of 8-oxodGuo compared to 8-oxodAdo. Interestingly, we show that >40% of the 8-oxodGuo involved in tandem lesions is refractory to excision by DNA glycosylases. Altogether our results demonstrate that, subsequently to a single oxidation event, peroxidation reactions significantly increase the yield of formation of hydroxylated purine modifications, generating a high proportion of tandem lesions partly refractory to base excision repair.

SUBMITTER: Bergeron F

PROVIDER: S-EPMC2851781 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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HO* radicals induce an unexpected high proportion of tandem base lesions refractory to repair by DNA glycosylases.

Bergeron François F Auvré Frédéric F Radicella J Pablo JP Ravanat Jean-Luc JL

Proceedings of the National Academy of Sciences of the United States of America 20100308 12

Reaction of HO(*) radicals with double-stranded calf thymus DNA produces high levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and, to a minor extent, 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodAdo). Formation of the hydroxylated purine lesions is explained by addition of HO(*) to the C8 position of the purine moiety. It has been reported that tandem lesions containing a formylamine residue neighboring 8-oxodGuo could be produced through addition of a transiently generated pyrimidine pe ...[more]

PMID: 20212167

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Project description:A growing number of iron-sulfur (Fe-S) cluster cofactors have been identified in DNA repair proteins. MutY and its homologs are base excision repair (BER) glycosylases that prevent mutations associated with the common oxidation product of guanine (G), 8-oxo-7,8-dihydroguanine (OG) by catalyzing adenine (A) base excision from inappropriately formed OG:A mispairs. The finding of an [4Fe-4S]2+ cluster cofactor in MutY, Endonuclease III, and structurally similar BER enzymes was surprising and initially thought to represent an example of a purely structural role for the cofactor. However, in the two decades subsequent to the initial discovery, purification and in vitro analysis of bacterial MutYs and mammalian homologs, such as human MUTYH and mouse Mutyh, have demonstrated that proper Fe-S cluster coordination is required for OG:A substrate recognition and adenine excision. In addition, the Fe-S cluster in MutY has been shown to be capable of redox chemistry in the presence of DNA. The work in our laboratory aimed at addressing the importance of the MutY Fe-S cluster has involved a battery of approaches, with the overarching hypothesis that understanding the role(s) of the Fe-S cluster is intimately associated with understanding the biological and chemical properties of MutY and its unique damaged DNA substrate as a whole. In this chapter, we focus on methods of enzyme expression and purification, detailed enzyme kinetics, and DNA affinity assays. The methods described herein have not only been leveraged to provide insight into the roles of the MutY Fe-S cluster but have also been provided crucial information needed to delineate the impact of inherited variants of the human homolog MUTYH associated with a colorectal cancer syndrome known as MUTYH-associated polyposis or MAP. Notably, many MAP-associated variants have been found adjacent to the Fe-S cluster further underscoring the intimate relationship between the cofactor, MUTYH-mediated DNA repair, and disease.

Project description:AimsCarotid reocclusion (CRO) after mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to tandem lesion (TL) or isolated internal carotid occlusion (ICO) is associated with worse clinical outcomes. Our aim was to analyze the predictors and clinical impact of CRO.MethodsA retrospective single-center analysis of all patients with anterior circulation strokes who underwent MT prospectively included in a registry between 2017 and 2020 was performed. ICO and TL as stroke causes were included. Stent deployment was left to the discretion of the interventionist. All patients received at least intravenous aspirin during MT. CRO was assessed using ultrasound within the first 24 h after MT. Efficacy and safety of stenting were assessed.ResultsAmong 1304 AIS cases, 218 (16.7%) were related to TL or ICO. Of them, 5% (n=11) were associated with internal CRO 24 h after the endovascular procedure. After adjusting per confounders, multivariate analysis showed that the independent variables associated with CRO were the TICI recanalization grade [TICI 2b-3; OR 0.1, 95% confidence interval (CI) 0.01-0.89, p=0.040], pial collateral circulation presence (OR 0.09, 95% CI 0.02-0.45, p=0.03), stent deployment during MT (OR 0.17, 95% CI 0.03-0.84, p=0.030), and general anesthesia use (OR 2.92, 95% CI 1.13-7.90, p=0.034). CRO showed a trend toward worst outcomes (modified Rankin scale 3-6) at 3 months (OR 3.4, 95% CI 0.96-12, p=0.057). After multivariate analysis, variables independently associated with worse outcomes at 90 days were intrastent platelet aggregation phenomena during endovascular therapy, admission National Institute of Health Stroke Scale, and age. Conversely, intravenous thrombolysis and TICI 2b-3 recanalization grade were identified as independent predictors of good outcomes at 90 days.ConclusionsCRO has a relevant clinical impact in our study, associating lower rates of good functional outcomes at 3 months. Independent factors of CRO were the recanalization degree, presence of pial collateral circulation, use of a stent as a protective factor, and use of general anesthesia during thrombectomy.

Dataset Information

HO* radicals induce an unexpected high proportion of tandem base lesions refractory to repair by DNA glycosylases.

Publications

HO* radicals induce an unexpected high proportion of tandem base lesions refractory to repair by DNA glycosylases.

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