Repair of DNA Damage Induced by Accelerated Heavy Ions in Mammalian Cells Proficient and Deficient in the Non-homologous End-Joining Pathway

Okayasu, Ryuichi; Okada, Maki; Okabe, Atsushi; Noguchi, Masafumi; Takakura, Kaoru; Takahashi, Sentaro

doi:10.1667/rr3489.1

Cited by 142 publications

(113 citation statements)

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“…A clonogenic survival assay was conducted as described previously (6). In brief, the appropriate plating density was designed to produce 20 to 40 surviving colonies in each 6-cm dish or T25 flask.…”

Section: Colony and Spheroid Formation Assaymentioning

confidence: 99%

“…High linear energy transfer (LET) particle therapy has various advantages because of the production of spread out Bragg's peaks (SOBP), which cover tumors with biologically equivalent dose distributions. Therefore, high LET heavy-ion therapy has several potential advantages over low LET photon therapy such as increased relative biological effect, reduced oxygen enhancement ratio, decreased cellcycle-dependent radiosensitivity, and induced complex DNA damage that is not easily repaired (5,6). Over the past decades, HIMAC has been successful in treating more than 5,000 cases of various human cancers and achieved promising clinical outcomes for many radioresistant tumor types, including recurrent colorectal cancer, hepatocellular carcinoma, chondroma, and sarcoma (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Carbon Ion Beam on Putative Colon Cancer Stem Cells and Its Comparison with X-rays

et al. 2011

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Section: Colony and Spheroid Formation Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Carbon Ion Beam on Putative Colon Cancer Stem Cells and Its Comparison with X-rays

et al. 2011

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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.…”

mentioning

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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“…The studies showed that clustered DSBs lesions induced by Fe particles are dif2icult to be repaired and resulting in elevated chromosome instability and enhanced cellular radiosensitivity (40,41) . The dif2iculty of repairing the clustered DSBs may due to the nature of the complex DNA damage induced by dense ionizations along the HZE particle track (19,22,(42)(43)(44)(45) . In mammalian cells, DNA DSBs are repaired mainly by two distinct pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR).…”

Section: The Repair Pathways Of Clustered Dna Damage Induced By Hze Pmentioning

confidence: 99%

The biological effects induced by high-charged and energy particles and its application in cancer therapy

Zhu

Ren

Chen

et al. 2016

IJRR

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The radiobiological effects of high atomic number and energy (HZE par cles) ion beams are of interest for radioprotec on in space and tumor radiotherapy. Space radia on mainly consists of heavy charged par cles from protons to iron ions, which is dis nct from common terrestrial forms of radia on. HZE par cles pose a significant cancer risk to astronauts on prolonged space missions. With high delivered energies and intense ioniza on, HZE par cles can damage not only the biological systems but also the shielding materials. HZE par cles are more effec ve than low-LET radia on like γ-or X-rays to induce gene c muta on and cancer. On Earth, similar ions are being used for targeted cancer therapy due to the advantage of the inverse dose profile, with delivering higher doses to the tumor while keeping lower doses to the surrounding ssues. In this review, we focus on the recent insights into the biological effects caused by HZE par cles and the corresponding mechanism. We also discuss the current applica on of HZE par cle in cancer therapy. Understanding the mechanisms underlying the repair of DNA damage induced by HZE par cles contribute to accurately es mate the risks to human health associated with HZE par cle exposure and to improve the effec veness of tumor radiotherapy.

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Repair of DNA Damage Induced by Accelerated Heavy Ions in Mammalian Cells Proficient and Deficient in the Non-homologous End-Joining Pathway

Cited by 142 publications

References 49 publications

Effects of Carbon Ion Beam on Putative Colon Cancer Stem Cells and Its Comparison with X-rays

Effects of Carbon Ion Beam on Putative Colon Cancer Stem Cells and Its Comparison with X-rays

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

The biological effects induced by high-charged and energy particles and its application in cancer therapy

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