Delayed repair of radiation induced clustered DNA damage: Friend or foe?

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

doi:10.1016/j.mrfmmm.2010.11.003

Cited by 208 publications

(184 citation statements)

References 74 publications

(98 reference statements)

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“…30,31 Left unrepaired, double-stranded DNA breaks can cause chromosomal instability and cell apoptosis. Incomplete repair leads to deletions and chromosomal rearrangements such as translocations and inversions that can ultimately lead to mutations.…”

Section: Discussionmentioning

confidence: 99%

Radiation Induced DNA Damage in Operators Performing Endovascular Aortic Repair

El-Sayed¹,

Patel²,

Cho³

et al. 2018

Journal of Vascular Surgery

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BACKGROUND:Radiation exposure during fluoroscopically guided interventions such as endovascular aortic repair (EVAR) is a growing concern for operators. This study aimed to measure DNA damage/repair markers in operators perfoming EVAR. METHODS:Expression of the DNA damage/repair marker, γ-H2AX and DNA damage response marker, phosphorylated ataxia telangiectasia mutated (pATM), were quantified in circulating lymphocytes in operators during the peri-operative period of endovascular (infrarenal, branched, and fenestrated) and open aortic repair using flow cytometry. These markers were separately measured in the same operators but this time wearing leg lead shielding in addition to upper body protection and compared with those operating with unprotected legs. Susceptibility to radiation damage was determined by irradiating operators' blood in vitro.RESULTS: γ-H2AX and pATM levels increased significantly in operators immediately after branched endovascular aortic repair/fenestrated endovascular aortic repair (P<0.0003 for both). Only pATM levels increased after infrarenal endovascular aortic repair (P<0.04). Expression of both markers fell to baseline in operators after 24 hours (P<0.003 for both). There was no change in γ-H2AX or pATM expression after open repair. Leg protection abrogated γ-H2AX and pATM response after branched endovascular aortic repair/fenestrated endovascular aortic repair. The expression of γ-H2AX varied significantly when operators' blood was exposed to the same radiation dose in vitro (P<0.0001).CONCLUSIONS: This is the first study to detect an acute DNA damage response in operators performing fluoroscopically guided aortic procedures and highlights the protective effect of leg shielding. Defining the relationship between this response and cancer risk may better inform safe levels of chronic low-dose radiation exposure. 1,2 The growing number and complexity of procedures means that interventionists are exposed to higher amounts of radiation, a subject that is becoming increasingly topical. Radiation-Induced3-7 A recently published 15-year follow-up study of the EVAR trial, comparing endovascular and open aortic repair, reported an increased incidence of malignancy in patients treated by EVAR. 8 There is, rightly so, a significant focus currently on reducing the patients' exposure to radiation, but mounting evidence suggests that recurrent lowdose exposure to the practitioner is equally as important. Robust data collection to assess the risks posed to the interventionist is in its infancy, but a number of studies suggest a link to adverse health effects, including a higher risk of posterior subcapsular lens changes and malignancy.9-11 One recent study found a higher incidence of malignancy, including brain cancer, breast cancer, and melanoma, in interventionists who performed fluoroscopically guided procedures compared with those who had never performed these.12 A better understanding of the hazards of occupational radiation exposure requires sensitive tools to measure exposure at an individu...

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Section: Discussionmentioning

confidence: 99%

Radiation Induced DNA Damage in Operators Performing Endovascular Aortic Repair

El-Sayed¹,

Patel²,

Cho³

et al. 2018

Journal of Vascular Surgery

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“…The induction of DSBs by oxidative stress is most likely a result of the processing of other types of DNA damage, including the repair of clustered lesions, breakage during the fragile blockage of replication forks by the lesions, 40,41 or the handling of DNA-DNA and DNA-protein crosslinks induced by ROS. 42 A second mechanism by which ROS leads to genomic instability is through the degradation of the anaphase blockers securin and cyclin B1, which impede aneuploidy by ensuring correct segregation of chromosomes during mitosis 43 and in checkpoint-arrested cells, thereby suspending the spindle checkpoint.…”

Section: Autophagy Mitochondria Metabolism and Tumorigenesismentioning

confidence: 99%

Autophagy and genomic integrity

et al. 2013

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DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.

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“…Interestingly, deletion mutants of EndoIII show a reduced formation of DSBs but are more sensitive to radiation (62)(63)(64)(65)(66). Eccles et al (67) discussed that repair of opposing DNA lesions by the BER pathway is slow and delayed and might induce DNA mutation or replication breakdown; however, if the opposing DNA lesions are incised only by EndoIII and not processed by the other BER proteins, a DSB which is repaired much faster occurs (67). The formation of DSBs caused by EndoIII might therefore actually be beneficial for the cells.…”

Section: Figmentioning

confidence: 99%

DNA Processing Proteins Involved in the UV-Induced Stress Response of Sulfolobales

Wolferen

Albers

2015

J Bacteriol

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The ups operon of Sulfolobus species is highly induced upon UV stress. Previous studies showed that the pili encoded by this operon are involved in cellular aggregation, which is essential for subsequent DNA exchange between cells, resulting in homologous recombination. The presence of this pilus system increases the fitness of Sulfolobus cells under UV light-induced stress conditions, as the transfer of DNA takes place in order to repair UV-induced DNA lesions via homologous recombination. Four conserved genes (saci_1497 to saci_1500) which encode proteins with putative DNA processing functions are present downstream of the ups operon. In this study, we show that after UV treatment the cellular aggregation of strains with saci_1497, saci_1498, and saci_1500 deletions is similar to that of wild-type strains; their survival rates, however, were reduced and similar to or lower than those of the pilus deletion strains, which could not aggregate anymore. DNA recombination assays indicated that saci_1498, encoding a ParB-like protein, plays an important role in DNA transfer. Moreover, biochemical analysis showed that the endonuclease III encoded by saci_1497 nicks UV-damaged DNA. In addition, RecQ-like helicase Saci_1500 is able to unwind homologous recombination intermediates, such as Holliday junctions. Interestingly, a saci_1500 deletion mutant was more sensitive to UV light but not to the replication-stalling agents hydroxyurea and methyl methanesulfonate, suggesting that Saci_1500 functions specifically in the UV damage pathway. Together these results suggest a role of Saci_1497 to Saci_1500 in the repair or transfer of DNA that takes place after UV-induced damage to the genomic DNA of Sulfolobus acidocaldarius. IMPORTANCESulfolobales species increase their fitness after UV stress by a UV-inducible pilus system that enables high rates of DNA exchange between cells. Downstream of the pilus operon, three genes that seem to play a role in the repair or transfer of the DNA between Sulfolobus cells were identified, and their possible functions are discussed. Next to the previously described role of UV-inducible pili in the exchange of DNA, we have thereby increased our knowledge of DNA transfer at the level of DNA processing. This paper therefore contributes to the overall understanding of the DNA exchange mechanism among Sulfolobales cells. In all domains of life, DNA repair is crucial for maintenance of genome integrity upon exposure to intra-or extracellular DNAdamaging threats (1). Unlike DNA repair in bacteria, archaeal DNA repair and its regulation are still far from well understood (1, 2). Homology searches revealed that the proteins in archaeal DNA repair pathways show similarities to both bacterial and eukaryotic proteins. In addition, DNA repair proteins with unique archaeal features exist (3).Previously, it was speculated that archaea might have SOS-like responses similar to those in certain bacteria (4); however, microarray studies revealed that neither Haloarchaea (5, 6) nor Sulfolobus species (7...

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Delayed repair of radiation induced clustered DNA damage: Friend or foe?

Cited by 208 publications

References 74 publications

Radiation Induced DNA Damage in Operators Performing Endovascular Aortic Repair

Radiation Induced DNA Damage in Operators Performing Endovascular Aortic Repair

Autophagy and genomic integrity

DNA Processing Proteins Involved in the UV-Induced Stress Response of Sulfolobales

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