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. Methods and Materials ATM- and H2AX-immunofluorescence was used to assess the number of recognized and unrepaired DSB in quiescent fibroblast cell lines exposed to x-rays, γ-rays, 9- and 12-MeV electrons, 3- and 65-MeV protons and 75-MeV/u carbon ions. Results The rate of radiation-induced ATM nucleo-shuttling was found to be specific to each radiation type tested. By increasing the permeability of the nuclear membrane with statin and bisphosphonates, 2 fibroblast cell lines exposed to high-LET particles were shown to be protected by an accelerated ATM nucleo-shuttling. Conclusions Our findings are in agreement with the conclusion that LET and the radiation/particle type influence the formation of ATM monomers in cytoplasm that are required for DSB recognition. A striking analogy was established between the DSB repair kinetics of radioresistant cells exposed to high-LET particles and that of several radiosensitive cells exposed to low-LET radiation. Our data show that the nucleo-shuttling of ATM provides crucial elements to predict radiation response in human quiescent cells, whatever the LET value and their radiosensitivity.
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 11 authors...
The tuberous sclerosis complex (TSC) syndrome is associated with numerous cutaneous pathologies (notably on the face), epilepsy, intellectual disability and developmental retardation and, overall, high occurrence of benign tumors in several organs, like angiofibromas, giant cell astrocytomas, renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis. TSC is caused by mutations of either of the hamartin or tuberin proteins that are mainly cytoplasmic. Some studies published in the 1980s repor...
#1Sandrine Pereira(French Institute of Health and Medical Research)H-Index: 23
#2Larry Bodgi(French Institute of Health and Medical Research)H-Index: 8
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 10 authors...
Purpose To examine the possibility of predicting clinical radiosensitivity by quantifying the nuclear forms of autophosphorylated ATM protein (pATM) via a specific enzyme-linked immunosorbent assay (ELISA). Methods and Materials This study was performed on 30 skin fibroblasts from 9 radioresistant patients and 21 patients with adverse tissue reaction events. Patients were divided into 2 groups: radioresistant (toxicity grade Results The pATM ELISA data were in quantitative agreement with the imm...
Last. Roger Williams(LMB: Laboratory of Molecular Biology)H-Index: 2
view all 10 authors...
ATM (ataxia-telangiectasia mutated) is a phosphatidylinositol 3-kinase–related protein kinase (PIKK) best known for its role in DNA damage response. ATM also functions in oxidative stress response, insulin signaling, and neurogenesis. Our electron cryomicroscopy (cryo-EM) suggests that human ATM is in a dynamic equilibrium between closed and open dimers. In the closed state, the PIKK regulatory domain blocks the peptide substrate–binding site, suggesting that this conformation may represent an i...
#1Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
#2Michel H. Bourguignon(Institut de radioprotection et de sûreté nucléaire)H-Index: 18
Last. Nobuyuki Hamada(CRIEPI: Central Research Institute of Electric Power Industry)H-Index: 33
view all 3 authors...
Abstract The human response to ionizing radiation (IR) varies among individuals. The first evidence of the individual response to IR was reported in the beginning of the 20th century. Considering nearly one century of observations, we here propose three aspects of individual IR response: radiosensitivity for early or late adverse tissue events after radiotherapy on normal tissues (non-cancer effects attributable to cell death); radiosusceptibility for IR-induced cancers; and radiodegeneration fo...
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 68 authors...
PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistan...
#1Larry Bodgi(French Institute of Health and Medical Research)H-Index: 8
#2Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
AbstractPurpose For 50 years, cellular radiosensitivity has been defined in vitro as the lack of clonogenic capacity of irradiated cells and its mathematical link with dose has been described by the target theory. Among the numerous formulas provided from the target theory, the linear-quadratic (LQ) model empirically describes cell survival as a negative exponential of a second degree polynomial dose-function in which αD is the linear component and βD2 is the quadratic one. The LQ model is exten...
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 14 authors...
Purpose After radiation therapy (RT), various radiation-induced toxicities can develop in about one-fourth of patients. An international interest in using morbidity and mortality rates to monitor the quality of care and integrate morbidity and mortality review (MMR) meetings into organizations' governance processes has arisen. We report the first results of patients included in our MMR procedure that included biological assays for individual intrinsic radiosensitivity (IIRS). Methods and Materia...
#1Tanya T. Paull(HHMI: Howard Hughes Medical Institute)H-Index: 56
The ataxia-telangiectasia mutated (ATM) protein kinase is a master regulator of the DNA damage response, and it coordinates checkpoint activation, DNA repair, and metabolic changes in eukaryotic cells in response to DNA double-strand breaks and oxidative stress. Loss of ATM activity in humans results in the pleiotropic neurodegeneration disorder ataxia-telangiectasia. ATM exists in an inactive state in resting cells but can be activated by the Mre11–Rad50–Nbs1 (MRN) complex and other factors at ...
#1Mélanie L. Ferlazzo(French Institute of Health and Medical Research)H-Index: 7
#2Laurène Sonzogni(French Institute of Health and Medical Research)H-Index: 3
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 9 authors...
Huntington’s disease (HD) is a neurodegenerative syndrome caused by mutations of the IT15 gene encoding for the huntingtin protein. Some research groups have previously shown that HD is associated with cellular radiosensitivity in quiescent cells. However, there is still no mechanistic model explaining such specific clinical feature. Here, we examined the ATM-dependent signaling and repair pathways of the DNA double-strand breaks (DSB), the key damage induced by ionizing radiation, in human HD s...
#1Larry Bodgi(French Institute of Health and Medical Research)H-Index: 8
#2Adeline Granzotto(French Institute of Health and Medical Research)H-Index: 9
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 10 authors...
Immunofluorescence with antibodies against DNA damage repair and signaling protein is revolutionar- ising the estimation of the genotoxic risk. Indeed, a number of stress response proteins relocalize in nucleus as identifiable foci whose number, pattern and appearance/disappearance rate depend on several parameters such as the stress nature, dose, time and individual factor. Few authors proposed biomathematical tools to describe them in a unified formula that would be relevant for all the reloca...
#1Anne-Sophie Wozny(CNRS: Centre national de la recherche scientifique)H-Index: 10
#2Arnaud Gauthier(CNRS: Centre national de la recherche scientifique)
Last. Dominique Ardail(CNRS: Centre national de la recherche scientifique)H-Index: 20
view all 12 authors...
Hypoxia-Inducible Factor 1α (HIF-1α), which promotes cancer cell survival, is the main regulator of oxygen homeostasis. Hypoxia combined with photon and carbon ion irradiation (C-ions) stabilizes HIF-1α. Silencing HIF-1α under hypoxia leads to substantial radiosensitization of Head-and-Neck Squamous Cell Carcinoma (HNSCC) cells after both photons and C-ions. Thus, this study aimed to clarify a potential involvement of HIF-1α in the detection, signaling, and repair of DNA Double-Strand-Breaks (DS...
Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was...
DNA double-strand breaks (DSBs) induced by photon irradiation are the most deleterious damage for cancer cells and their efficient repair may contribute to radioresistance, particularly in hypoxic conditions. Carbon ions (C-ions) act independently of the oxygen concentration and trigger complex- and clustered-DSBs difficult to repair. Understanding the interrelation between hypoxia, radiation-type, and DNA-repair is therefore essential for overcoming radioresistance. The DSBs signaling and the c...
#1Mélanie L. Ferlazzo(French Institute of Health and Medical Research)H-Index: 7
#2Elise Berthel(French Institute of Health and Medical Research)H-Index: 5
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 11 authors...
AbstractPurpose: Xeroderma Pigmentosum (XP) is a rare, recessive genetic disease associated with photosensitivity, skin cancer proneness, neurological abnormalities and impaired nucleotide excision...
AbstractPurpose: Humans are increasingly exposed to ionising radiation (IR). Both low (<100 mGy) and high doses can cause stochastic effects, including cancer; whereas doses above 100 mGy are neede...
#1Elise Berthel(French Institute of Health and Medical Research)H-Index: 5
#2Mélanie L. Ferlazzo(French Institute of Health and Medical Research)H-Index: 7
Last. Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
view all 5 authors...
Our understanding of the molecular and cellular response to ionizing radiation (IR) has progressed considerably. This is notably the case for the repair and signaling of DNA double-strand breaks (DSB) that, if unrepaired, can result in cell lethality, or if misrepaired, can cause cancer. However, through the different protocols, techniques, and cellular models used during the last four decades, the DSB repair kinetics and the relationship between cellular radiosensitivity and unrepaired DSB has ...
#1Elise Berthel(French Institute of Health and Medical Research)H-Index: 5
#2Nicolas Foray(French Institute of Health and Medical Research)H-Index: 30
Last. Mélanie L. Ferlazzo(French Institute of Health and Medical Research)H-Index: 7
view all 3 authors...
The evaluation of radiation-induced (RI) risks is of medical, scientific, and societal interest. However, despite considerable efforts, there is neither consensual mechanistic models nor predictive assays for describing the three major RI effects, namely radiosensitivity, radiosusceptibility, and radiodegeneration. Interestingly, the ataxia telangiectasia mutated (ATM) protein is a major stress response factor involved in the DNA repair and signaling that appears upstream most of pathways involv...