DNA Double-Strand Breaks Repair and Signaling of Human Gliomas and Normal Brain Cells in Response to Radiation: Potential Impact of the ATM-and BRCA1- Dependent Pathways

Granzotto, Adeline; Bencokova, Zuzana; Vogin, Guillaume; Devic, Clément; Joubert, Aurélie; Balosso, Jacques; Foray, Nicolas

doi:10.5772/19475

Cited by 9 publications

(14 citation statements)

References 39 publications

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“…The ATM nucleoshuttling, quantified by the number of nuclear foci formed by the auto-transphosphorylation forms of ATM (pATM), was shown to be the basis of powerful predictive assays. [12][13][14][15][16][17][18] This model is consistent with the findings that ATM monomers are more active than ATM dimers. 19,20 Furthermore, the ATM nucleo-shuttling model provides a novel biological interpretation of the linear-quadratic formula that is also consistent with the hypersensitivity to the low-dose phenomenon.…”

Section: Introductionsupporting

confidence: 88%

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation

Maalouf

Granzotto

Devic

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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The nucleo-shuttling of the ATM protein has recently been shown to influence the individual response to Purpose: Linear energy transfer (LET) plays an important role in radiation response. Recently, the radiation-induced nucleo-shuttling of ATM from cytoplasm to the nucleus was shown to be a major event of the radiation response that permits a normal DNA double-strand break (DSB) recognition and repair. Here, we aimed to verify the relevance of the ATM nucleo-shuttling model for high-LET particles and various radiation types.

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Section: Introductionsupporting

confidence: 88%

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation

Maalouf

Granzotto

Devic

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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“…To this aim, we assessed the number of γH2AX foci and micronuclei remaining after metal exposure for 24 h in three human nontransformed astrocyte cell lines and one endothelial cell line. These brain cell lines were provided from the cortex (Ha), the hippocampus (Hah), and the spinal cord (Hasp) from the same donor and were shown to elicit different delays of RIANS [55]. The 149BR fibroblast cell line served as a control (Figure 1).…”

Section: Cell-type Dependence In the Response To Metal Exposurementioning

confidence: 99%

DNA Double-Strand Breaks Induced in Human Cells by Twelve Metallic Species: Quantitative Inter-Comparisons and Influence of the ATM Protein

et al. 2021

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Despite a considerable amount of data, the molecular and cellular bases of the toxicity due to metal exposure remain unknown. Recent mechanistic models from radiobiology have emerged, pointing out that the radiation-induced nucleo-shuttling of the ATM protein (RIANS) initiates the recognition and the repair of DNA double-strand breaks (DSB) and the final response to genotoxic stress. In order to document the role of ATM-dependent DSB repair and signalling after metal exposure, we applied twelve different metal species representing nine elements (Al, Cu, Zn Ni, Pd, Cd, Pb, Cr, and Fe) to human skin, mammary, and brain cells. Our findings suggest that metals may directly or indirectly induce DSB at a rate that depends on the metal properties and concentration, and tissue type. At specific metal concentration ranges, the nucleo-shuttling of ATM can be delayed which impairs DSB recognition and repair and contributes to toxicity and carcinogenicity. Interestingly, as observed after low doses of ionizing radiation, some phenomena equivalent to the biological response observed at high metal concentrations may occur at lower concentrations. A general mechanistic model of the biological response to metal exposure based on the nucleo-shuttling of ATM is proposed to describe the metal-induced stress response and to define quantitative endpoints for toxicity and carcinogenicity.

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“…However, we did not observe significant changes in Caspase3 and BRCA1, which verified the decitabine-induced Caspase-independent apoptotic response and impaired BRCA1-pathway in human gliomas. 50, 51 The induction of p53 and p21 could in turn retard cell cycle progression and cell proliferation. Examined by flow cytometry, a much larger proportion of cells were found to be arrested in the G2/M-phase when subjected to combinatorial treatment (Figure 7B), which is in agreement with the previous research on decitabine pharmacology.…”

Section: Resultsmentioning

confidence: 99%

Decitabine Nanoconjugate Sensitizes Human Glioblastoma Cells to Temozolomide

Cui¹,

Naz

Thompson³

et al. 2015

Mol. Pharmaceutics

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In this study we developed and characterized a delivery system for the epigenetic demethylating drug, decitabine, to sensitize temozolomide-resistant human glioblastoma multiforme (GBM) cells to alkylating chemotherapy. A poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) based nano-conjugate was fabricated to encapsulate decitabine and achieved a better therapeutic response in GBM cells. After synthesis, the highly efficient uptake process and intracellular dynamics of this nano-conjugate was monitored by single-molecule fluorescence tools. Our experiments demonstrated that, under an acidic pH due to active glycolysis in cancer cells, the PLGA-PEG nano-vector could release the conjugated decitabine at a faster rate, after which the hydrolyzed lactic acid and glycolic acid would further acidify the intracellular microenvironment, thus providing a “positive feedback” to increase the effective drug concentration and realize growth inhibition. In temozolomide-resistant GBM cells, decitabine can potentiate the cytotoxic DNA alkylation by counteracting cytosine methylation and reactivating tumor suppressor genes, such as p53 and p21. Owing to excellent internalization and endo-lysosomal escape enabled by the PLGA-PEG backbone, the encapsulated decitabine exhibited a better anti-GBM potential than free drug molecules. Hence, the synthesized nano-conjugate and temozolomide could act in synergy to deliver a more potent and long-term anti-proliferation effect against malignant GBM cells.

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DNA Double-Strand Breaks Repair and Signaling of Human Gliomas and Normal Brain Cells in Response to Radiation: Potential Impact of the ATM-and BRCA1- Dependent Pathways

Cited by 9 publications

References 39 publications

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation

Influence of Linear Energy Transfer on the Nucleo-shuttling of the ATM Protein: A Novel Biological Interpretation Relevant for Particles and Radiation

DNA Double-Strand Breaks Induced in Human Cells by Twelve Metallic Species: Quantitative Inter-Comparisons and Influence of the ATM Protein

Decitabine Nanoconjugate Sensitizes Human Glioblastoma Cells to Temozolomide

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