The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation

Wang, Hongyan; Wang, Xiang; Zhang, Piyan; Wang, Ya

doi:10.1016/j.dnarep.2008.01.010

Cited by 110 publications

(130 citation statements)

References 32 publications

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“…It has been reported that clustered DNA damage is induced by high-LET radiation, and that the induced DSBs or DNA fragments are not efficiently repaired (Pastwa et al, 2003;Suzuki et al, 2006;Tsuruoka et al, 2008). This phenomenon possibly correlates with an inefficiency of the C-NHEJ pathway at DSBs induced by high-LET radiation (Wang et al, 2008(Wang et al, , 2010. In support of this theory, it was found that an A. thaliana DNA ligase IV mutant, deficient in the C-NHEJ pathway, was more sensitive to 113 keV lm À1 C-ion irradiation than to 425 keV lm À1 compared with the wild type (Hase et al, 2012).…”

Section: Discussionmentioning

confidence: 91%

Comprehensive identification of mutations induced by heavy‐ion beam irradiation in Arabidopsis thaliana

et al. 2015

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SUMMARYHeavy-ion beams are widely used for mutation breeding and molecular biology. Although the mutagenic effects of heavy-ion beam irradiation have been characterized by sequence analysis of some restricted chromosomal regions or loci, there have been no evaluations at the whole-genome level or of the detailed genomic rearrangements in the mutant genomes. In this study, using array comparative genomic hybridization (array-CGH) and resequencing, we comprehensively characterized the mutations in Arabidopsis thaliana genomes irradiated with Ar or Fe ions. We subsequently used this information to investigate the mutagenic effects of the heavy-ion beams. Array-CGH demonstrated that the average number of deleted areas per genome were 1.9 and 3.7 following Ar-ion and Fe-ion irradiation, respectively, with deletion sizes ranging from 149 to 602 180 bp; 81% of the deletions were accompanied by genomic rearrangements. To provide a further detailed analysis, the genomes of the mutants induced by Ar-ion beam irradiation were resequenced, and total mutations, including base substitutions, duplications, in/dels, inversions, and translocations, were detected using three algorithms. All three resequenced mutants had genomic rearrangements. Of the 22 DNA fragments that contributed to the rearrangements, 19 fragments were responsible for the intrachromosomal rearrangements, and multiple rearrangements were formed in the localized regions of the chromosomes. The interchromosomal rearrangements were detected in the multiply rearranged regions. These results indicate that the heavy-ion beams led to clustered DNA damage in the chromosome, and that they have great potential to induce complicated intrachromosomal rearrangements. Heavy-ion beams will prove useful as unique mutagens for plant breeding and the establishment of mutant lines.

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Section: Discussionmentioning

confidence: 91%

Comprehensive identification of mutations induced by heavy‐ion beam irradiation in Arabidopsis thaliana

et al. 2015

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“…Recently our group and others showed that high LET IR killing more cells than low LET IR is mainly due to the inhibition of Ku-dependent NHEJ. 5,6 After induction of DSBs, proliferating cells actively slow down cell cycle progression via checkpoint activation to provide time for repair. Previously, we and others showed that IR-induced checkpoint response mainly promotes HRR and has little effect on NHEJ.…”

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confidence: 99%

Checkpoint response plays a more protective role in HZE particle-irradiated cells than in X ray-irradiated cells

Wang¹,

Wang²

2008

Cell Cycle

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High linear energy transfer (LET) ionizing radiation (IR) kills more cells as compared with low LET IR at the same doses. High LET IR is induced by high-charge (HZE) particles (a component in space radiation), high energy ions or by a special clinical radiotherapy machine. Low LET IR includes X or γ ray (a major component of IR from standard clinical radiotherapy machines), etc. The more cell death induced by high LET IR than by low LET IR at the same dose reflects a relative biological effectiveness (RBE). RBE on all kinds of quantitative effects induced by IR in X-ray exposed cells is 1. The RBE of cell killing induced by high LET IR is ~2-4 in cultured cells (killing ~2-4 times the number of cells at the same dose) depending on cell type. The induction of DNA double strand breaks (DSBs) either by high LET IR or by low-LET IR is a severe threat to genomic integrity that determines radiosensitivity (short term effect) and carcinogenesis (long term effect). It is believed that the higher RBE on cell killing by high LET IR is because of ineffective rejoining of DNA DSBs. [1][2][3][4] Two major DNA DSB repair pathways exist in eukaryotic cells, homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Recently our group and others showed that high LET IR killing more cells than low LET IR is mainly due to the inhibition of Ku-dependent NHEJ. 5,6 After induction of DSBs, proliferating cells actively slow down cell cycle progression via checkpoint activation to provide time for repair. Previously, we and others showed that IR-induced checkpoint response mainly promotes HRR and has little effect on NHEJ. 7-10 These results provide important information that because the NHEJ pathway is inhibited in high LET irradiated cells, HRR might play a more protective role in such cells than that in low LET irradiated cells; because checkpoint facilitates mainly the HRR pathway, checkpoint response might be a more efficient factor for modifying cell sensitivity to high LET IR than to low LET IR. To test this hypothesis, we examined and analyzed the RBE on sensitivity in ATM or ATR, the two most important checkpoint genes, deficient or kinase dead cell lines following either high LET or low LET IR. The results support our hypothesis: both the cell lines either deficient in ATM or with kinase dead ATR, show higher RBE than their wild type counterpart cells (Fig. 1A and B). The RBE difference at 2 Gy is 3 times between AT cells and their wild type counterpart and is 5 times between ATR cells and their wild type counterpart (Fig. 1C). These results indicate that checkpoint response plays a more protective role in HZE particleirradiated cells than in X ray-irradiated cells, suggesting that checkpoint response is a more efficient target for modifying cell sensitivity to high LET IR than that to low LET IR.

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“…In mammalian cells, the relative biological effectiveness (RBE), which is a ratio of the biological effects generated by high linear energy transfer (LET) radiation to low LET reference radiation, ranges from 2 to 6 [27]. However, in an NHEJ-deficient genetic background, where HR is the main mechanism for repair, the RBE for high LET radiation is close to 1 [28][29]. This suggests that NHEJ is the most prominent DNA repair pathway of radiation-induced DNA DSBs.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Radiosensitization of Gemcitabine Related to Suppression of a Repair Pathway: Examination of Mammalian Cells with Therapeutic High Energy X-rays

Morikawa¹

2017

AJLM

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Abstract:Gemcitabine is used in clinical chemo-radiotherapy; however, the mechanism underlying enhanced radiosensitivity by gemcitabine is not fully elucidated. We evaluated the role of gemcitabine in mammalian cell lines using a therapeutic high energy 10 MeV linac-X-ray irradiation device. Rodent cell lines CHO and xrs5 were used. A total of 5 µM gemcitabine for 24 hours was administered with or without post-X-ray irradiation. DNA double-strand breaks (DSBs) and cell enlargement were observed by using singly gemcitabine. Enhanced cell killing effects by radiotherapy were observed with gemcitabine pre-treatment in both CHO and xrs5 cells. We focused on the dynamics of phosphorylated p53-binding protein 1 (53BP1)-positive foci after irradiation. Significantly higher numbers of 53BP1 foci were observed after irradiation in gemcitabine pre-treated cells than in untreated cells. The radiosensitizing effect of gemcitabine was not suppressed in the non-homologous end joining (NHEJ) deficient xrs5 cells. We confirmed that in rodent cells the radiosensitizing effect of gemcitabine is related to suppression of a repair pathway other than NHEJ.

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The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation

Cited by 110 publications

References 32 publications

Comprehensive identification of mutations induced by heavy‐ion beam irradiation in Arabidopsis thaliana

Comprehensive identification of mutations induced by heavy‐ion beam irradiation in Arabidopsis thaliana

Checkpoint response plays a more protective role in HZE particle-irradiated cells than in X ray-irradiated cells

The Effect of Radiosensitization of Gemcitabine Related to Suppression of a Repair Pathway: Examination of Mammalian Cells with Therapeutic High Energy X-rays

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