Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET Radiation
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 po...
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MDPI AG
2021-06-01
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| Online Access: | https://www.mdpi.com/2075-1729/11/6/560 |
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| author | Veronika Mladenova Emil Mladenov Michael Scholz Martin Stuschke George Iliakis |
| author_facet | Veronika Mladenova Emil Mladenov Michael Scholz Martin Stuschke George Iliakis |
| author_sort | Veronika Mladenova |
| collection | DOAJ |
| description | 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 <sup>56</sup>Fe 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 <sup>56</sup>Fe ions show an enhanced G<sub>2</sub>-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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| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-10T10:25:45Z |
| publishDate | 2021-06-01 |
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| series | Life |
| spelling | doaj.art-d1701c779b3b4e00a94f1e88a926d3632023-11-22T00:03:50ZengMDPI AGLife2075-17292021-06-0111656010.3390/life11060560Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET RadiationVeronika Mladenova0Emil Mladenov1Michael Scholz2Martin Stuschke3George Iliakis4Department of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, GermanyDepartment of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, GermanyBiophysics Division, GSI Helmholtzzentrum für Schwerionenforschung GmbH, 64291 Darmstadt, GermanyDepartment of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, GermanyDepartment of Radiation Therapy, Division of Experimental Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, GermanyThe 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 <sup>56</sup>Fe 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 <sup>56</sup>Fe ions show an enhanced G<sub>2</sub>-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.https://www.mdpi.com/2075-1729/11/6/560ionizing radiation (IR)heavy ionsalpha particleshigh-LET radiationstructural chromosomal abnormalities (SCAs) |
| spellingShingle | Veronika Mladenova Emil Mladenov Michael Scholz Martin Stuschke George Iliakis Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET Radiation Life ionizing radiation (IR) heavy ions alpha particles high-LET radiation structural chromosomal abnormalities (SCAs) |
| title | Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET Radiation |
| title_full | Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET Radiation |
| title_fullStr | Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET Radiation |
| title_full_unstemmed | Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET Radiation |
| title_short | Strong Shift to ATR-Dependent Regulation of the G<sub>2</sub>-Checkpoint after Exposure to High-LET Radiation |
| title_sort | strong shift to atr dependent regulation of the g sub 2 sub checkpoint after exposure to high let radiation |
| topic | ionizing radiation (IR) heavy ions alpha particles high-LET radiation structural chromosomal abnormalities (SCAs) |
| url | https://www.mdpi.com/2075-1729/11/6/560 |
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