Processing of a complex multiply damaged DNA site by human cell extracts and purified repair proteins

Éot-Houllier, Grégory; Eon-Marchais, Séverine; Gasparutto, Didier; Sage, Évelyne

doi:10.1093/nar/gki165

Cited by 76 publications

(92 citation statements)

References 44 publications

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“…They are likely to consist of closely spaced SSBs together with oxidative base damages and/or complex DSBs. Several model studies suggested that some combinations of lesions may be lethal and even mutagenic (David-Cordonnier et al 2000Harrison and Malyarchuk 2002;Harrison et al 1999;Eot-Houllier et al 2005;Budworth et al 2005). At the cellular level, LMDS were thought to be detectable, after conversion into DSBs by specific DNA glycosylases (Fpg) and/or endonucleases (Nth, Nfo) through selective cuts at oxidatively damaged sites in opposite DNA strands, using conventional pulsed-field gel electrophoresis (Sutherland et al 2000).…”

Section: Importance Of Radiolesions Induced At Low Dosesmentioning

confidence: 99%

Does Scientific Evidence Support a Change From the LNT Model for Low-Dose Radiation Risk Extrapolation?

Averbeck¹

2009

Health Physics

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The linear no-threshold (LNT) model has been widely used to establish international rules and standards in radiation protection. It is based on the notion that the physical energy deposition of ionizing radiation (IR) increases carcinogenic risk linearly with increasing dose (i.e., the carcinogenic effectiveness remains constant irrespective of dose) and, within a factor of two, also with dose-rate. However, recent findings have strongly put into question the LNT concept and its scientific validity, especially for very low doses and dose-rates. Low-dose effects are more difficult to ascertain than high-dose effects. Epidemiological studies usually lack sufficient statistical power to determine health risks from very low-dose exposures. In this situation, studies of the fundamental mechanisms involved help to understand and assess short- and long-term effects of low-dose IR and to evaluate low-dose radiation risks. Several lines of evidence demonstrate that low-dose and low dose-rate effects are generally lower than expected from high-dose exposures. DNA damage signaling, cell cycle checkpoint activation, DNA repair, gene and protein expression, apoptosis, and cell transformation differ qualitatively and quantitatively at high- and low-dose IR exposures, and most animal and epidemiological data support this conclusion. Thus, LNT appears to be scientifically invalid in the low-dose range.

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Section: Importance Of Radiolesions Induced At Low Dosesmentioning

confidence: 99%

Does Scientific Evidence Support a Change From the LNT Model for Low-Dose Radiation Risk Extrapolation?

Averbeck¹

2009

Health Physics

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“…Experimental studies suggest much slower rejoining kinetics for DSBs induced by high-LET radiations compared with low-LET radiations (25,26) reflecting the increased complexity of DSBs induced by high-LET radiation (27). Studies with synthetic oligonucleotides containing specific types of clusters suggest that clustered DNA lesions are resistant to processing by glycosylases or endonucleases (28)(29)(30)(31)(32)(33). In vivo studies have shown that the number of abasic clusters formed in human monocytes after irradiation did not return to background levels for over 14 days (14).…”

Section: Introductionmentioning

confidence: 99%

Induction and Processing of Oxidative Clustered DNA Lesions in⁵⁶Fe-Ion-Irradiated Human Monocytes

et al. 2007

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Space and cosmic radiation is characterized by energetic heavy ions of high linear energy transfer (LET). Although both low- and high-LET radiations can create oxidative clustered DNA lesions and double-strand breaks (DSBs), the local complexity of oxidative clustered DNA lesions tends to increase with increasing LET. We irradiated 28SC human monocytes with doses from 0-10 Gy of (56)Fe ions (1.046 GeV/ nucleon, LET = 148 keV/microm) and determined the induction and processing of prompt DSBs and oxidative clustered DNA lesions using pulsed-field gel electrophoresis (PFGE) and Number Average Length Analysis (NALA). The (56)Fe ions produced decreased yields of DSBs (10.9 DSB Gy(-1) Gbp(-1)) and clusters (1 DSB: approximately 0.8 Fpg clusters: approximately 0.7 Endo III clusters: approximately 0.5 Endo IV clusters) compared to previous results with (137)Cs gamma rays. The difference in the relative biological effectiveness (RBE) of the measured and predicted DSB yields may be due to the formation of spatially correlated DSBs (regionally multiply damaged sites) which result in small DNA fragments that are difficult to detect with the PFGE assay. The processing data suggest enhanced difficulty compared with gamma rays in the processing of DSBs but not clusters. At the same time, apoptosis is increased compared to that seen with gamma rays. The enhanced levels of apoptosis observed after exposure to (56)Fe ions may be due to the elimination of cells carrying high levels of persistent DNA clusters that are removed only by cell death and/or "splitting" during DNA replication.

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“…Removal of damage in LMDS has been shown to be less efficient than that of single lesions (17)(18)(19). Moreover, as a consequence of their repair, LMDS can induce highly genotoxic double-strand breaks (20,21). In the case of tandem lesions that could be considered as a class of LMDS in which the two modifications are adjacent to each other and located on the same strand, the presence of thymidine glycols (ThdGly) neighboring 8-oxodGuo has been shown to modulate the efficacy of excision of the oxidized purine by its specific human glycosylase hOGG1 (22).…”

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confidence: 99%

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

Bergeron

Auvré

Radicella

et al. 2010

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

124

113

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Reaction of HO• radicals with double-stranded calf thymus DNA produces high levels of and, to a minor extent, . 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 ≈10% of the total 8-oxodGuo. In the present work we show that addition of HO • onto the C8 of purine accounts for only ∼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.DNA damage | DNA repair | peroxidation reaction | tandem lesions F ormation of oxidatively generated DNA lesions is associated with the occurrence of degenerative diseases, cancer, and aging (1). Therefore, reactions of reactive oxygen species, and among them the highly genotoxic hydroxyl radical (HO • ), with DNA constituents have been extensively studied during the last three decades (2). 8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and, to a minor extent the corresponding adenine derivative 8-oxo-7,8-dihydro-2′-deoxyadenosine (8-oxodAdo), have been shown to be significantly generated in cellular DNA under various conditions of oxidative stress. More than 20 years ago (3) it was established that in the presence of HO• (produced either by the indirect effect of ionizing radiation or by Fenton-type reactions) the mechanism of formation of 8-hydroxylated purine lesions (8-oxoPur), including both 8-oxodGuo and 8-oxodAdo, involves addition of HO• to the C8 position of the purine bases, followed by an oxidation reaction (for a review see refs. 2 and 4). In addition, 8-oxoPur could be also produced by a one-electron oxidation process followed by hydration of the purine radical cation thus generated, producing following oxidation mainly 8-oxodGuo due to efficient charge transfer processes (5, 6) combined with the relatively low ionization potential of guanine compared to other DNA constituents.In addition, the pioneering work of Box and coworkers (7-10) suggested the possible formation of tandem lesions, constituted of two adjacent modifications. Recent works have demonstrated that in dinucleoside monophosp...

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Processing of a complex multiply damaged DNA site by human cell extracts and purified repair proteins

Cited by 76 publications

References 44 publications

Does Scientific Evidence Support a Change From the LNT Model for Low-Dose Radiation Risk Extrapolation?

Does Scientific Evidence Support a Change From the LNT Model for Low-Dose Radiation Risk Extrapolation?

Induction and Processing of Oxidative Clustered DNA Lesions in⁵⁶Fe-Ion-Irradiated Human Monocytes

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

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Processing of a complex multiply damaged DNA site by human cell extracts and purified repair proteins

Cited by 76 publications

References 44 publications

Does Scientific Evidence Support a Change From the LNT Model for Low-Dose Radiation Risk Extrapolation?

Does Scientific Evidence Support a Change From the LNT Model for Low-Dose Radiation Risk Extrapolation?

Induction and Processing of Oxidative Clustered DNA Lesions in56Fe-Ion-Irradiated Human Monocytes

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

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Induction and Processing of Oxidative Clustered DNA Lesions in⁵⁶Fe-Ion-Irradiated Human Monocytes

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