scholarly journals Influence of Individual Radiosensitivity on the Hormesis Phenomenon: Toward a Mechanistic Explanation Based on the Nucleoshuttling of ATM Protein

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091378
Author(s):  
Clément Devic ◽  
Mélanie L. Ferlazzo ◽  
Elise Berthel ◽  
Nicolas Foray
Keyword(s):  
Low Dose ◽  
Molecular Model ◽  
Dose Range ◽  
Mechanistic Explanation ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Cellular Models ◽  
Individual Radiosensitivity ◽  
Biological Interpretation ◽  
Atm Protein

Hormesis is a low-dose phenomenon that has been reported to occur, to different extents, in animals, plants, and microorganisms. However, a review of the literature shows that only a few reports describe it in humans. Also, the diversity of experimental protocols and cellular models used makes deciphering the mechanisms of hormesis difficult. In humans, hormesis mostly appears in the 20 to 75 mGy dose range and in nontransformed, radioresistant cells. In a previous paper by Devic et al, a biological interpretation of the adaptive response (AR) phenomenon was proposed using our model that is based on the radiation-induced nucleoshuttling of the ATM protein (the RIANS model). Here, we showed that the 20 to 75 mGy dose range corresponds to a maximum amount of ATM monomers diffusing into the nucleus, while no DNA double-strand breaks is produced by radiation. These ATM monomers are suggested to help in recognizing and repairing spontaneous DNA breaks accumulated in cells and contribute to reductions in genomic instability and aging. The RIANS model also permitted the biological interpretation of hypersensitivity to low doses (HRS)—another low-dose phenomenon. Hence, for the first time to our knowledge, hormesis, AR, and HRS can be explained using the same unified molecular model.

scholarly journals Influence of Individual Radiosensitivity on the Adaptive Response Phenomenon: Toward a Mechanistic Explanation Based on the Nucleo-Shuttling of ATM Protein

Dose-Response ◽  
2018 ◽  
Vol 16 (3) ◽  
pp. 155932581878983 ◽  
Author(s):  
Clément Devic ◽  
Mélanie L. Ferlazzo ◽  
Nicolas Foray
Keyword(s):  
Adaptive Response ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mechanistic Model ◽  
Mechanistic Explanation ◽  
Human Cells ◽  
Cellular Models ◽  
Individual Radiosensitivity ◽  
Challenging Dose ◽  
Atm Protein

The adaptive response (AR) phenomenon generally describes a protective effect caused by a “priming” low dose ( dAR) delivered after a period of time (Δ tAR) before a higher “challenging” dose ( DAR). The AR is currently observed in human cells if dAR, Δ tAR, and DAR belong to (0.001-0.5 Gy), (2-24 hours), (0.1-5 Gy), respectively. In order to investigate the molecular mechanisms specific to AR in human cells, we have systematically reviewed the experimental AR protocols, the cellular models, and the biological endpoints used from the 1980s. The AR appears to be preferentially observed in radiosensitive cells and is strongly dependent on individual radiosensitivity. To date, the model of the nucleo-shuttling of the ATM protein provides a relevant mechanistic explanation of the AR molecular and cellular events. Indeed, the priming dose dAR may result in the diffusion of a significant amount of active ATM monomers in the nucleus. These ATM monomers, added to those induced directly by the challenging dose DAR, may increase the efficiency of the response to DAR by a better ATM-dependent DNA damage recognition. Such mechanistic model would also explain why AR is not observed in radioresistant or hyperradiosensitive cells. Further investigations at low dose are needed to consolidate our hypotheses.

scholarly journals Effects of gamma-radiation on DNA damage in onion (Allium cepa L.) seedlings

2019 ◽  
Vol 489 (2) ◽  
pp. 199-204
Author(s):  
A. Ya. Bolsunovsky ◽  
D. V. Dementyev ◽  
T. S. Frolova ◽  
E. A. Trofimova ◽  
E. M. Iniatkina ◽  
...  
Keyword(s):  
Dna Damage ◽  
Comet Assay ◽  
Gamma Radiation ◽  
Allium Cepa ◽  
Low Dose ◽  
Nuclear Dna ◽  
Biological Effects ◽  
Dose Range ◽  
Dna Breaks ◽  
Allium Test

The effect of -radiation on the level of nuclear DNA damage in onion seedlings (Allium-test) was studied using the comet assay. DNA breaks were first found in cells of onion seedlings exposed to low-dose radiation ( 0,1 Gy). Dose dependence of DNA damage parameters showed nonlinear behavior: a linear section in the low-dose region (below 0,1 Gy) and a dose-independent plateau in the dose range between 1 and 5 Gy. Thus, the comet assay can be used to estimate the biological effects of low-dose gamma-radiation on Allium cepa seedlings.

scholarly journals Accumulation of Temozolomide-Induced Apoptosis, Senescence and DNA Damage by Metronomic Dose Schedule: A Proof-of-Principle Study with Glioblastoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6287
Author(s):  
Lea Beltzig ◽  
Björn Stratenwerth ◽  
Bernd Kaina
Keyword(s):  
Cumulative Dose ◽  
Low Dose ◽  
Dose Range ◽  
Dose Schedule ◽  
Dna Double Strand Breaks ◽  
Glioblastoma Cells ◽  
Response Curves ◽  
Therapy Targets ◽  
Induced Apoptosis

Temozolomide (TMZ), a first-line drug in glioma therapy, targets the tumor DNA at various sites. One of the DNA alkylation products is O6-methylguanine (O6MeG), which is, in the low dose range of TMZ, responsible for nearly all genotoxic and cytotoxic effects relevant for cancer therapy. There is, however, a dispute regarding whether the TMZ concentration in the tumor tissue in patients is sufficient to elicit a significant cytotoxic or cytostatic response. Although treatment with TMZ occurs repeatedly with daily doses (metronomic dose schedule) and in view of the short half-life of the drug it is unclear whether doses are accumulating. Here, we addressed the question whether repeated low doses elicit similar effects in glioblastoma cells than a high cumulative dose. We show that repeated treatments with a low dose of TMZ (5 × 5 µM) caused an accumulation of cytotoxicity through apoptosis, cytostasis through cellular senescence, and DNA double-strand breaks, which was similar to the responses induced by a single cumulative dose of 25 µM TMZ. This finding, together with the previously reported linear dose–response curves, support the notion that TMZ is able to trigger a significant cytotoxic and cytostatic effect in vivo if the low-dose metronomic schedule is applied.

scholarly journals Small tandem DNA duplications result from CST-guided Pol α-primase action at DNA break termini

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joost Schimmel ◽  
Núria Muñoz-Subirana ◽  
Hanneke Kool ◽  
Robin van Schendel ◽  
Marcel Tijsterman
Keyword(s):  
Mechanistic Explanation ◽  
Underlying Mechanism ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Dna Break ◽  
Non Homologous End Joining ◽  
Tandem Duplications

AbstractSmall tandem duplications of DNA occur frequently in the human genome and are implicated in the aetiology of certain human cancers. Recent studies have suggested that DNA double-strand breaks are causal to this mutational class, but the underlying mechanism remains elusive. Here, we identify a crucial role for DNA polymerase α (Pol α)-primase in tandem duplication formation at breaks having complementary 3′ ssDNA protrusions. By including so-called primase deserts in CRISPR/Cas9-induced DNA break configurations, we reveal that fill-in synthesis preferentially starts at the 3′ tip, and find this activity to be dependent on 53BP1, and the CTC1-STN1-TEN1 (CST) and Shieldin complexes. This axis generates near-blunt ends specifically at DNA breaks with 3′ overhangs, which are subsequently repaired by non-homologous end-joining. Our study provides a mechanistic explanation for a mutational signature abundantly observed in the genomes of species and cancer cells.

scholarly journals The Nucleoshuttling of the ATM Protein: A Unified Model to Describe the Individual Response to High- and Low-Dose of Radiation?

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 905 ◽  
Author(s):  
Elise Berthel ◽  
Nicolas Foray ◽  
Mélanie L. Ferlazzo
Keyword(s):  
Low Dose ◽  
Protein A ◽  
Individual Response ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Cytoplasmic Proteins ◽  
Radiation Induced ◽  
Atm Protein ◽  
The Individual ◽  
Predictive Assays

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 involved in the three precited RI effects. The rate of the RI ATM nucleoshuttling (RIANS) was shown to be a good predictor of radiosensitivity. In the frame of the RIANS model, irradiation triggers the monomerization of cytoplasmic ATM dimers, which allows ATM monomers to diffuse in nucleus. The nuclear ATM monomers phosphorylate the H2AX histones, which triggers the recognition of DNA double-strand breaks and their repair. The RIANS model has made it possible to define three subgroups of radiosensitivity and provided a relevant explanation for the radiosensitivity observed in syndromes caused by mutated cytoplasmic proteins. Interestingly, hyper-radiosensitivity to a low dose and adaptive response phenomena may be also explained by the RIANS model. In this review, the relevance of the RIANS model to describe several features of the individual response to radiation was discussed.

scholarly journals Skin regeneration is accelerated by a lower dose of multipotent mesenchymal stromal/stem cells—a paradigm change

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gertraud Eylert ◽  
Reinhard Dolp ◽  
Alexandra Parousis ◽  
Richard Cheng ◽  
Christopher Auger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Low Dose ◽  
Dose Range ◽  
High Dose ◽  
Full Thickness ◽  
Burn Wound ◽  
Dermal Regeneration Template ◽  
Yorkshire Pigs ◽  
Stromal Stem Cells

Abstract Background Multipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®. Methods We conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin. Result We found that the low dose range between 200 and 40,000 cells/cm2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000–400,000 cells/cm2 and a high dose of 2,000,000 cells/cm2. The low dose of 40,000 cells/cm2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control. Conclusion This regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome.

Induction and Repair of DNA Double-Strand Breaks in the Same Dose Range as the Shoulder of the Survival Curve

1994 ◽  
Vol 140 (2) ◽  
pp. 161 ◽  
Author(s):  
Barbara Nevaldine ◽  
John A. Longo ◽  
Michael Vilenchik ◽  
Gerald A. King ◽  
Peter J. Hahn
Keyword(s):  
Survival Curve ◽  
Dose Range ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

scholarly journals The Role of RNA in DNA Breaks, Repair and Chromosomal Rearrangements

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 550
Author(s):  
Matvey Mikhailovich Murashko ◽  
Ekaterina Mikhailovna Stasevich ◽  
Anton Markovich Schwartz ◽  
Dmitriy Vladimirovich Kuprash ◽  
Aksinya Nicolaevna Uvarova ◽  
...  
Keyword(s):  
Chromosomal Rearrangements ◽  
Gene Mutations ◽  
Nonhomologous End Joining ◽  
Published Data ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
End Joining ◽  
Homology Directed Repair ◽  
Chromosome Aberration Frequency

Incorrect reparation of DNA double-strand breaks (DSB) leading to chromosomal rearrangements is one of oncogenesis’s primary causes. Recently published data elucidate the key role of various types of RNA in DSB formation, recognition and repair. With growing interest in RNA biology, increasing RNAs are classified as crucial at the different stages of the main pathways of DSB repair in eukaryotic cells: nonhomologous end joining (NHEJ) and homology-directed repair (HDR). Gene mutations or variation in expression levels of such RNAs can lead to local DNA repair defects, increasing the chromosome aberration frequency. Moreover, it was demonstrated that some RNAs could stimulate long-range chromosomal rearrangements. In this review, we discuss recent evidence demonstrating the role of various RNAs in DSB formation and repair. We also consider how RNA may mediate certain chromosomal rearrangements in a sequence-specific manner.

scholarly journals Genetic Separation of Sae2 Nuclease Activity from Mre11 Nuclease Functions in Budding Yeast

2017 ◽  
Vol 37 (24) ◽  
Author(s):  
Sucheta Arora ◽  
Rajashree A. Deshpande ◽  
Martin Budd ◽  
Judy Campbell ◽  
America Revere ◽  
...  
Keyword(s):  
Nuclease Activity ◽  
Double Strand Breaks ◽  
Endonuclease Activity ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Content Type ◽  
Strand Breaks ◽  
Dna Ends

ABSTRACT Sae2 promotes the repair of DNA double-strand breaks in Saccharomyces cerevisiae. The role of Sae2 is linked to the Mre11/Rad50/Xrs2 (MRX) complex, which is important for the processing of DNA ends into single-stranded substrates for homologous recombination. Sae2 has intrinsic endonuclease activity, but the role of this activity has not been assessed independently from its functions in promoting Mre11 nuclease activity. Here we identify and characterize separation-of-function mutants that lack intrinsic nuclease activity or the ability to promote Mre11 endonucleolytic activity. We find that the ability of Sae2 to promote MRX nuclease functions is important for DNA damage survival, particularly in the absence of Dna2 nuclease activity. In contrast, Sae2 nuclease activity is essential for DNA repair when the Mre11 nuclease is compromised. Resection of DNA breaks is impaired when either Sae2 activity is blocked, suggesting roles for both Mre11 and Sae2 nuclease activities in promoting the processing of DNA ends in vivo. Finally, both activities of Sae2 are important for sporulation, indicating that the processing of meiotic breaks requires both Mre11 and Sae2 nuclease activities.

scholarly journals DETERMINATION OF ELECTRON BEAM CHARGING CONDITIONS OF OXIDES AT LOW ENERGY IN THE LOW DOSE RANGE

1989 ◽  
Vol 50 (C6) ◽  
pp. C6-174-C6-174
Author(s):  
M. VALENZA ◽  
P. GIRARD ◽  
B. PISTOULET
Keyword(s):  
Electron Beam ◽  
Low Dose ◽  
Dose Range ◽  
Low Energy
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