Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage

Eccles, Laura J.; Lomax, Martine E.; O’Neill, Peter

doi:10.1093/nar/gkp1070

Cited by 68 publications

(68 citation statements)

References 63 publications

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“…These repair centers once formed are considered to be the signature of IR and they are often associated with resistance to repair and proneness to errors and misrepair [55]. Substantial evidence suggests that it is not only the prompt (direct) DSBs formed by IR that have implications on cell survival and genomic instability, but also the conversion of non-DSB clusters into DSBs during processing and attempted repair [56]. This possibility is high especially when the two non-DSB lesions are located in a distance of up to 10 bp [56].…”

Section: Discussionmentioning

confidence: 99%

Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)

Nikitaki

Nikolov

Mavragani

et al. 2016

Free Radical Research

105

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Detrimental effects of ionizing radiation (IR) are correlated to the varying efficiency of IR to induce complex DNA damage. A double strand break (DSB) can be considered the simpler form of complex DNA damage. These types of damage can consist of DSBs, single strand breaks (SSBs) and/or non-DSB lesions such as base damages and apurinic/apyrimidinic (AP; abasic) sites in different combinations. Enthralling theoretical (Monte Carlo simulations) and experimental evidence suggests an increase in the complexity of DNA damage and therefore repair resistance with linear energy transfer (LET). In this study, we have measured the induction and processing of DSB and non-DSB oxidative clusters using adaptations of immunofluorescence. Specifically, we applied foci colocalization approaches as the most current methodologies for the in situ detection of clustered DNA lesions in a variety of human normal (FEP18-11-T1) and cancerous cell lines of varying repair efficiency (MCF7, HepG2, A549, MO59K/J) and radiation qualities of increasing LET, that is c-, X-rays 0.3-1 keV/lm, a-particles 116 keV/lm and 36 Ar ions 270 keV/lm. Using c-H2AX or 53BP1 foci staining as DSB probes, we calculated a DSB apparent rate of 5-16 DSBs/cell/Gy decreasing with LET. A similar trend was measured for non-DSB oxidized base lesions detected using antibodies against the human repair enzymes 8-oxoguanine-DNA glycosylase (OGG1) or AP endonuclease (APE1), that is damage foci as probes for oxidized purines or abasic sites, respectively. In addition, using colocalization parameters previously introduced by our groups, we detected an increasing clustering of damage for DSBs and non-DSBs. We also make correlations of damage complexity with the repair efficiency of each cell line and we discuss the biological importance of these new findings with regard to the severity of IR due to the complex nature of its DNA damage. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)

Nikitaki

Nikolov

Mavragani

et al. 2016

Free Radical Research

105

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“…Moreover, we studied the influence of the in situ formation of cytotoxic ROS formed by BSAO and spermine to differentiate the MDR response in contrast with wild-type human tumor cell lines. Ionising radiation induces clustered DNA damage, defined as two or more lesions within one or two helical turns of the DNA double-helix by a single radiation track (28,29). The primary cellular repair mechanism is the base excision repair (BER) pathway to repair base lesions, AP sites and SSBs which are induced in cells either endogenously or by IR (30,31).…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments

Amendola

Cervelli

Fratini

et al. 2013

International Journal of Oncology

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Abstract.The most frequent interventions in cancer therapy are currently the destruction of cells by irradiation or administration of drugs both able to induce radical formation and toxic metabolites by enzyme-catalyzed reactions. The aim of this study was to determine the cell viability of cells undergoing a DNA damage threshold accomplished by ROS overproduction via both ectopic expression of murine spermine oxidase (mSMOX) and bovine serum amine oxidase (BSAO) enzymes. Low dose of X-irradiation delivers a challenging dose of damage as evaluated in proficient Chinese hamster AA8 cell line and both deficient transcription-coupled nucleotide excision repair (NER) UV61 cells and deficient base excision repair (BER) EM9 cells, at 6 and 24 h after exposure. The priming dose of ROS overexposure by mSMOX provokes an adaptive response in N18TG2, AA8 and EM9 cell lines at 24 h. Interestingly, in the UV61 cells, ROS overexposure by mSMOX delivers an earlier adaptive response to radiation. The enzymatic formation of toxic metabolites has mainly been investigated on wild-type (WT) and multidrug-resistant (MDR) cancer cell lines, using and spermine as substrate of the BSAO enzyme. MDR cells are more sensitive to the toxic polyamine metabolites than WT cells, thus indicating a new therapeutic strategy to overcome MDR tumors. Since SMOX in mammals is differentially activated in a tissue-specific manner and cancer cells can differ in terms of DNA repair and MDR capabilities, it could be of interest to simultaneously treat with very low dose of X-rays and/or to alter SMOX metabolism to generate a differential response in healthy and cancer tissues. IntroductionMammalian cells evolved and constantly live in a highly reactive oxidative environment. In the mammalian organism H 2 O 2 has a central position within the reactive oxygen species (ROS) family. Its formation by several reactions and its controlled inactivation is the basis of redox homeostasis (1,2), since free radicals are highly cytotoxic. Oxidative stress is the result of interactions with macromolecules among highly reactive hydrogen peroxide (H 2 O 2 ) and singlet oxygen ( ). Besides the major interest in identification and advancement of compounds which are either radical scavengers or antioxidants, ROS can alternate between a positive and negative cellular outcomes (3). Insufficient ROS defense mechanisms are mutagenic and promote cell death, apoptosis and autophagy (4). Recently autophagy and apoptosis stimulus by the presence of an H 2 O 2 -induced pathway in human primary and tumor cell lines and in primary cells (5)

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“…RBE for hatchability based on ED 37 values was 4.5 in C. elegans (Table 1). Studies in cultured mammalian cells suggest that compared to low-LET radiation, high-LET radiation induces more complex DNA damage, what is called clustered DNA damage (Eccles et al, 2010). Especially, high-LET radiation at about 100 keV/µm has the greatest biological effects .…”

Section: Dose Response For Hatchabilitymentioning

confidence: 99%

Behavioral Resistance of Caenorhabditis elegans Against High-LET Radiation Exposure

et al. 2012

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Effects of high linear energy transfer (LET) radiation on the functions of the nervous system is a potential risk in interplanetary manned space missions. However, little is known about how the ner vous system is protected against high-LET radiation exposure. The analysis of high-LET radiation resistant animals would be therefore important for space missions. Here, we investigated the resistance to high-LET radiation exposure for two behaviors of the nematode, Caenorhabditis elegans, which is known as a model organism for the nervous system. Tested behaviors were locomotion and chemotaxis to NaCl. In addition, egg hatchability was examined as an indicator of high-LET radiation sensitivity. Relative biological effectiveness (RBE) of high-LET radiation ( 12 C, 18.3 MeV/u, LET = 113 keV/ µm) relative to low-LET radiation for hatchability was 4.5, whereas RBEs for locomotion and chemotaxis were 1.4 and 1.1, respectively. This study shows that the behavioral system for locomotion and chemotaxis of C. elegans is highly resistant to high-LET radiation exposure.

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Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage

Cited by 68 publications

References 63 publications

Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)

Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)

Reactive oxygen species spermine metabolites generated from amine oxidases and radiation represent a therapeutic gain in cancer treatments

Behavioral Resistance of Caenorhabditis elegans Against High-LET Radiation Exposure

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