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Stochastic multicellular modeling of x-ray irradiation, DNA damage induction, DNA free-end misrejoining and cell death.

ABSTRACT: The repair or misrepair of DNA double-strand breaks (DSBs) largely determines whether a cell will survive radiation insult or die. A new computational model of multicellular, track structure-based and pO₂-dependent radiation-induced cell death was developed and used to investigate the contribution to cell killing by the mechanism of DNA free-end misrejoining for low-LET radiation. A simulated tumor of 1224 squamous cells was irradiated with 6 MV x-rays using the Monte Carlo toolkit Geant4 with low-energy Geant4-DNA physics and chemistry modules up to a uniform dose of 1?Gy. DNA damage including DSBs were simulated from ionizations, excitations and hydroxyl radical interactions along track segments through cell nuclei, with a higher cellular pO₂ enhancing the conversion of DNA radicals to strand breaks. DNA free-ends produced by complex DSBs (cDSBs) were able to misrejoin and produce exchange-type chromosome aberrations, some of which were asymmetric and lethal. A sensitivity analysis was performed and conditions of full oxia and anoxia were simulated. The linear component of cell killing from misrejoining was consistently small compared to values in the literature for the linear component of cell killing for head and neck squamous cell carcinoma (HNSCC). This indicated that misrejoinings involving DSBs from the same x-ray (including all associated secondary electrons) were rare and that other mechanisms (e.g. unrejoined ends) may be important. Ignoring the contribution by the indirect effect toward DNA damage caused the DSB yield to drop to a third of its original value and the cDSB yield to drop to a tenth of its original value. Track structure-based cell killing was simulated in all 135306 viable cells of a 1?mm³ hypoxic HNSCC tumor for a uniform dose of 1?Gy.

SUBMITTER: Forster JC

PROVIDER: S-EPMC6906404 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Stochastic multicellular modeling of x-ray irradiation, DNA damage induction, DNA free-end misrejoining and cell death.

Forster Jake C JC Douglass Michael J J MJJ Phillips Wendy M WM Bezak Eva E

Scientific reports 20191211 1

The repair or misrepair of DNA double-strand breaks (DSBs) largely determines whether a cell will survive radiation insult or die. A new computational model of multicellular, track structure-based and pO<sub>2</sub>-dependent radiation-induced cell death was developed and used to investigate the contribution to cell killing by the mechanism of DNA free-end misrejoining for low-LET radiation. A simulated tumor of 1224 squamous cells was irradiated with 6 MV x-rays using the Monte Carlo toolkit Ge ...[more]

PMID: 31827107

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Project description:Non?small cell lung cancer (NSCLC) is radioresistant to X?rays due to powerful cellular DNA damage repair mechanisms. DNA?dependent protein kinase (DNA?PK) is a key enzyme involved in DNA damage repair and the phenomenon and molecular mechanism of NSCLC radionsensitivity were investigated following inhibition of DNA?PK activity. In the present study A549 cells were treated with the DNA?PK inhibitor NU7026 and/or siRNA directed against ataxia telangiectasia mutated (ATM), followed by exposure to 4 Gy X?ray irradiation. Radiosensitivity, DNA damage, apoptosis and protein expression were measured by colony formation assay, ?H2AX foci immunofluorescence, Annexin V/PI staining and western blotting, respectively. A Balb/c?nu/nu xenograft mouse model was established by subcutaneous injection of A549 cells and was used to examine the effect of administering NU7026 via intraperitoneal injection prior to 4 Gy X?ray exposure. The xenograft tumors were weighed and observed by hematoxylin and eosin staining after irradiation. NU7026 treatment followed by X?ray irradiation significantly decreased the colony formation ratio of A549 cells, and increased ?H2AX foci and cell apoptosis. Furthermore, the combined treatment of NU7026 and X?rays resulted in growth inhibition and cell apoptosis in A549 xenograft tumors. Consequently, apoptosis regulators full?length transactivating (TA) p73 and an N?terminally truncated (DN) p73 were upregulated and downregulated respectively, leading to activation of glucosyltransferases and Rab?like GTPase activators and myotubularins domain?containing 4 (GRAMD4) protein to reduce the Bcl?2/Bax protein ratio. In addition, ATM siRNA efficiently prevented ?H2AX foci formation, and enhanced NU7026?induced inhibition of survival and promoted apoptosis. In conclusion, inhibition of DNA?PK activity increased the radiosensitivity of A549 cells to X?ray irradiation. NU7026 treatment activated the ATM?dependent DNA damage response and induced p73 apoptosis pathway. DNA?PK inhibitor may be an effective constituent of radiosensitization products. DNA damage repair pathway could be a potential target for radiosensitization.

Dataset Information

Stochastic multicellular modeling of x-ray irradiation, DNA damage induction, DNA free-end misrejoining and cell death.

Publications

Stochastic multicellular modeling of x-ray irradiation, DNA damage induction, DNA free-end misrejoining and cell death.

Similar Datasets

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