Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations

Sun, Jiying; Shi, Lin; Kinomura, Aiko; Fukuto, Atsuhiko; Horikoshi, Yasunori; Oma, Yukako; Harata, Masahiko; Ikura, Masae; Ikura, Tsuyoshi; Kanaar, Roland; Tashiro, Satoshi

doi:10.7554/elife.32222

Cited by 5 publications

(4 citation statements)

References 58 publications

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“…Our observations are also in line with previous studies showing that the transient inhibition of ATM causes the accumulation of persistent chromosome aberrations [44,45]. Inhibition of ATM suppresses the formation of IR-induced sister chromatid exchanges (SCEs), a process attributed to homologous recombination-mediated repair [46].…”

Section: Let-dependent Radiosensitization and Sca Induction By Atmi O...supporting

confidence: 92%

“…Inhibition of ATM suppresses the formation of IR-induced sister chromatid exchanges (SCEs), a process attributed to homologous recombination-mediated repair [46]. ATM deficiency also causes 11q23 chromosome translocations-the most frequent chromosome abnormality in secondary leukemia [44]. It is likely that the decreased fidelity of DSB repair by the inappropriate regulation of HR that leads to the engagement of alt-EJ in ATM-inhibited cells increases the incidence of SCAs after exposure to low-LET IR.…”

Section: Let-dependent Radiosensitization and Sca Induction By Atmi O...mentioning

confidence: 99%

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Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation

Mladenova

Mladenov

Scholz

et al. 2021

Life

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The utilization of high linear-energy-transfer (LET) ionizing radiation (IR) modalities is rapidly growing worldwide, causing excitement but also raising concerns, because our understanding of their biological effects is incomplete. Charged particles such as protons and heavy ions have increasing potential in cancer therapy, due to their advantageous physical properties over X-rays (photons), but are also present in the space environment, adding to the health risks of space missions. Therapy improvements and the protection of humans during space travel will benefit from a better understanding of the mechanisms underpinning the biological effects of high-LET IR. There is evidence that high-LET IR induces DNA double-strand breaks (DSBs) of increasing complexity, causing enhanced cell killing, owing, at least partly, to the frequent engagement of a low-fidelity DSB-repair pathway: alternative end-joining (alt-EJ), which is known to frequently induce severe structural chromosomal abnormalities (SCAs). Here, we evaluate the radiosensitivity of A549 lung adenocarcinoma cells to X-rays, α-particles and 56Fe ions, as well as of HCT116 colorectal cancer cells to X-rays and α-particles. We observe the expected increase in cell killing following high-LET irradiation that correlates with the increased formation of SCAs as detected by mFISH. Furthermore, we report that cells exposed to low doses of α-particles and 56Fe ions show an enhanced G2-checkpoint response which is mainly regulated by ATR, rather than the coordinated ATM/ATR-dependent regulation observed after exposure to low doses of X-rays. These observations advance our understanding of the mechanisms underpinning high-LET IR effects, and suggest the potential utility for ATR inhibitors in high-LET radiation therapy.

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Section: Let-dependent Radiosensitization and Sca Induction By Atmi O...supporting

confidence: 92%

Section: Let-dependent Radiosensitization and Sca Induction By Atmi O...mentioning

confidence: 99%

Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation

Mladenova

Mladenov

Scholz

et al. 2021

Life

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“…We noted the shared upregulation of AATF, which is involved in inhibiting p53-mediated induction of apoptotic genes after DNA damage suggesting shared anti-apoptotic pathways 55 . DNA repair genes were also shared, including ACTR8 which plays a role in ssDNA synthesis during double-strand breaks during homologous recombination 56 , 57 . Similarly, a structural maintenance complex gene, SMC5, with roles in homologous recombination, was also upregulated 58 as well as PIF1 , a DNA synthesis stimulator during break-induced replication 59 .…”

Section: Resultsmentioning

confidence: 99%

Investigating the effects of chronic low-dose radiation exposure in the liver of a hypothermic zebrafish model

Cahill

Silveira

Renaud

et al. 2023

Sci Rep

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Mankind’s quest for a manned mission to Mars is placing increased emphasis on the development of innovative radio-protective countermeasures for long-term space travel. Hibernation confers radio-protective effects in hibernating animals, and this has led to the investigation of synthetic torpor to mitigate the deleterious effects of chronic low-dose-rate radiation exposure. Here we describe an induced torpor model we developed using the zebrafish. We explored the effects of radiation exposure on this model with a focus on the liver. Transcriptomic and behavioural analyses were performed. Radiation exposure resulted in transcriptomic perturbations in lipid metabolism and absorption, wound healing, immune response, and fibrogenic pathways. Induced torpor reduced metabolism and increased pro-survival, anti-apoptotic, and DNA repair pathways. Coupled with radiation exposure, induced torpor led to a stress response but also revealed maintenance of DNA repair mechanisms, pro-survival and anti-apoptotic signals. To further characterise our model of induced torpor, the zebrafish model was compared with hepatic transcriptomic data from hibernating grizzly bears (Ursus arctos horribilis) and active controls revealing conserved responses in gene expression associated with anti-apoptotic processes, DNA damage repair, cell survival, proliferation, and antioxidant response. Similarly, the radiation group was compared with space-flown mice revealing shared changes in lipid metabolism.

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“…Immunofluorescence staining was performed as described previously ( 18 ) . Briefly, cells were fixed in 4% paraformaldehyde in PBS for 10 minutes at room temperature, and then permeabilized with 0.5% Triton X-100 in PBS for 10 minutes at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Klotho protects chromosomal DNA from radiation-induced damage

Nakayama

Sun

Horikoshi

et al. 2023

The Journal of Biochemistry

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Klotho is an anti-aging, single-pass transmembrane protein found mainly in the kidney. Although aging is likely to be associated with DNA damage, the involvement of Klotho in protecting cells from DNA damage is still unclear. In this study, we examined DNA damage in human kidney cells and mouse kidney tissue after ionizing radiation (IR). The depletion and overexpression of Klotho in human kidney cells reduced and increased the cell survival rates after IR, respectively. The formation of γ-H2AX foci, representing DNA damage, was significantly elevated immediately after IR in cells with Klotho depletion and decreased in cells overexpressing Klotho. These results were confirmed in mouse renal tissues after IR. Quantification of DNA damage by a comet assay revealed that the Klotho knockdown significantly increased the amount of DNA damage immediately after IR, suggesting that Klotho protects chromosomal DNA from the induction of damage, rather than facilitating DNA repair. Consistent with this notion, Klotho was detected in both the nucleus and cytoplasm. In the nucleus, Klotho may serve to protect chromosomal DNA from damage, leading to its anti-aging effects.

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Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations

Cited by 5 publications

References 58 publications

Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation

Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation

Investigating the effects of chronic low-dose radiation exposure in the liver of a hypothermic zebrafish model

Klotho protects chromosomal DNA from radiation-induced damage

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