The nucleo-shuttling of the ATM protein as a basis for a novel theory of radiation response: resolution of the linear-quadratic model*

Bodgi, Larry; Foray, Nicolas

doi:10.3109/09553002.2016.1135260

Cited by 92 publications

(168 citation statements)

References 47 publications

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“…Besides, there is previous evidence that BRCA1 and BRCA2 are required for genome surveillance and repair of several DNA damage types, notably DSB (Venkitaraman, 2002;Powell and Kachnic, 2003). Hence, from the mechanistic model described above (Bodgi and Foray, 2016) mutations in tumor suppressor proteins may lead to overexpression of non-functional proteins in cytoplasm that prevent a rapid ATM nucleo-shuttling induced by radiation. The hypersensitivity to low-dose exposure can therefore be particularly observed in cells from high family risk women, mutated or not (Colin et al, 2011b).…”

Section: Radiobiological Study Using Non-tumoral Breast Epithelial Cellsmentioning

confidence: 98%

“…The ATM protein kinase is a central component of a signal transduction process that responds to DNA DSB by contributing to the phosphorylation of the H2AX histone variant (gH2AX). Recently, a molecular explanation of the hyper-recombination and hypersensitivity to low-dose exposure was proposed (Bodgi and Foray, 2016): the delay of translocation of ATM from the cytoplasm to the nucleus. In essence, the ATM protein kinase, a major actor of the response to radiation, is mainly localized in the cytoplasm as a dimeric and inactive form.…”

Section: Radiobiological Study Using Non-tumoral Breast Epithelial Cellsmentioning

confidence: 99%

“…In the case of low-doses ionizing radiation the amount of monomeric ATM forms can be too low to recognize the radiation-induced DSB. For some gene mutations and some individual status, this specific low-dose phenomenon can be particularly exacerbated: low-dose can induce unrepaired DSB (then participating to cell lethality) or misrepaired DNA (then participating to carcinogenesis) (Bodgi and Foray, 2016). Numerous tumor suppressor proteins interact with ATM in cytoplasm, notably BRCA1, BRCA2 and p53, all involved in the response to radiation.…”

Section: Radiobiological Study Using Non-tumoral Breast Epithelial Cellsmentioning

confidence: 99%

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Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review

et al. 2017

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-The aim of this review paper is to clarify the radio-induced breast cancer (BC) risk in BRCA mutation carriers with a combined epidemiological and radiobiological comprehensive approach. A systematic literature search on PubMed (MEDLINE) and EMBASE was performed for articles published from January 1st, 2000 to June 15th, 2017 using dedicated key words as subject headings (MeSH) in three domains of research and evaluation: risk modeling, cohort-studies and ex-vivo radiation biology with epithelial non-tumoral human breast cells. Only eleven articles that meet the selection criteria could be retrieved. These articles are analyzed and discussed. This review, which includes all types of radiological breast exposures, shows an association between BC risk and low cumulative X-ray doses before age 30. There is no consistent data in this literature regarding the risk of BC from radiological exposure after age 30. Biological data point out strong indicators of radiation-induced genomic instability linked with carcinogenesis pathways. We conclude that the risk of radio-induced BC in BRCA mutation carriers depends on age at exposure and that repeated X-ray breast exposures such as mammography should be used very cautiously in these mutated patients.

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Section: Radiobiological Study Using Non-tumoral Breast Epithelial Cellsmentioning

confidence: 98%

Section: Radiobiological Study Using Non-tumoral Breast Epithelial Cellsmentioning

confidence: 99%

Section: Radiobiological Study Using Non-tumoral Breast Epithelial Cellsmentioning

confidence: 99%

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Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review

et al. 2017

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“…Whether the initial rapid activation of ATM in response to DSBs occurs primarily in the nucleus, as has been widely assumed based on a number of reports that ATM in non-stressed cells is primarily nuclear [e.g., (81)], or whether it occurs in the cytoplasm (82), requires clarification. Of note, ATM also undergoes additional post-translational modifications in the course of the DDR, including acetylation by Tip60 (HIV-1 Tat interacting protein 60 kDa), which links the DDR to the chromatin remodeling that is important for repair (83).…”

Section: The Atm Proteinmentioning

confidence: 99%

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

2018

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There has been enormous recent progress in understanding how human cells respond to oxidative stress, such as that caused by exposure to ionizing radiation. We have witnessed a significant deciphering of the events that underlie how antioxidant responses counter pro-oxidant damage to key biological targets in all cellular compartments, including the genome and mitochondria. These cytoprotective responses include: 1. The basal cellular repertoire of antioxidant capabilities and its supporting cast of facilitator enzymes; and 2. The inducible phase of the antioxidant response, notably that mediated by the Nrf2 transcription factor. There has also been frenetic progress in defining how reactive electrophilic species swamp existing protective mechanisms to augment DNA damage, events that are embodied in the cellular “DNA-damage response”, including cell cycle checkpoint activation and DNA repair, which occur on a time scale of hours to days, as well as the implementation of cellular responses such as apoptosis, autophagy, senescence and reprograming that extend the time period of damage sensing and response into weeks, months and years. It has become apparent that, in addition to the initial oxidative insult, cells typically undergo further waves of secondary reactive oxygen/nitrogen species generation, DNA damage and signaling and that these may reemerge long after the initial events have subsided, probably being driven, at least in part, by persisting DNA damage. These reactive oxygen/nitrogen species are an integral part of the pathological consequences of radiation exposure and may persist across multiple cell divisions. Because of the pervasive nature of oxidative stress, a cell will manifest different responses in different subcellular compartments and to different levels of stress injury. Aspects of these compartmentalized responses can involve the same proteins (such as ATM, p53 and p21) but in different functional guises, e.g., in cytoplasmic versus nuclear responses or in early-versus late-phase events. Many of these responses involve gene activation and new protein synthesis as well as a plethora of post-translational modifications of both basal and induced response proteins. It is these responses that we focus on in this review.

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“…With this in mind, one should pay attention to the interpretation made by Foray and coll. where α represents recognized but non-repaired damages and β non-recognized therefore non-repaired damages (Bodgi and Foray, 2016).…”

Section: What About Dna Damage?mentioning

confidence: 99%

Actual questions raised by nanoparticle radiosensitization

Brun

Sicard-Roselli

2016

Radiation Physics and Chemistry

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The nucleo-shuttling of the ATM protein as a basis for a novel theory of radiation response: resolution of the linear-quadratic model*

Abstract: Our model provides a very general picture of human radiosensitivity, independently of the dose, the cell type and the genetic status.

Cited by 92 publications

References 47 publications

Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review

Radiation induced breast cancer risk in BRCA mutation carriers from low-dose radiological exposures: a systematic review

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

Actual questions raised by nanoparticle radiosensitization

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