International Journal of Molecular Sciences

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4 pages, 198 KiB

Open AccessEditorial

Radiation Damage in Biomolecules and Cells 2.0

by Mario P. Carante, Ricardo L. Ramos and Francesca Ballarini

Int. J. Mol. Sci. 2023, 24(4), 3238; https://doi.org/10.3390/ijms24043238 - 6 Feb 2023

Cited by 1 | Viewed by 1495

Abstract

It is well known that ionizing radiation, when it hits living cells, causes a plethora of different damage types at different levels [...] Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

Research

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19 pages, 3869 KiB

Open AccessArticle

From Double-Strand Break Recognition to Cell-Cycle Checkpoint Activation: High Content and Resolution Image Cytometry Unmasks 53BP1 Multiple Roles in DNA Damage Response and p53 Action

by Laura Furia, Simone Pelicci, Mirco Scanarini, Pier Giuseppe Pelicci and Mario Faretta

Int. J. Mol. Sci. 2022, 23(17), 10193; https://doi.org/10.3390/ijms231710193 - 5 Sep 2022

Cited by 4 | Viewed by 2325

Abstract

53BP1 protein has been isolated in-vitro as a putative p53 interactor. From the discovery of its engagement in the DNA-Damage Response (DDR), its role in sustaining the activity of the p53-regulated transcriptional program has been frequently under-evaluated, even in the case of a [...] Read more.

53BP1 protein has been isolated in-vitro as a putative p53 interactor. From the discovery of its engagement in the DNA-Damage Response (DDR), its role in sustaining the activity of the p53-regulated transcriptional program has been frequently under-evaluated, even in the case of a specific response to numerous DNA Double-Strand Breaks (DSBs), i.e., exposure to ionizing radiation. The localization of 53BP1 protein constitutes a key to decipher the network of activities exerted in response to stress. We present here an automated-microscopy for image cytometry protocol to analyze the evolution of the DDR, and to demonstrate how 53BP1 moved from damaged sites, where the well-known interaction with the DSB marker γH2A.X takes place, to nucleoplasm, interacting with p53, and enhancing the transcriptional regulation of the guardian of the genome protein. Molecular interactions have been quantitatively described and spatiotemporally localized at the highest spatial resolution by a simultaneous analysis of the impairment of the cell-cycle progression. Thanks to the high statistical sampling of the presented protocol, we provide a detailed quantitative description of the molecular events following the DSBs formation. Single-Molecule Localization Microscopy (SMLM) Analysis finally confirmed the p53–53BP1 interaction on the tens of nanometers scale during the distinct phases of the response. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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17 pages, 4765 KiB

Open AccessArticle

Nanoscale Calculation of Proton-Induced DNA Damage Using a Chromatin Geometry Model with Geant4-DNA

by Kun Zhu, Chun Wu, Xiaoyu Peng, Xuantao Ji, Siyuan Luo, Yuchen Liu and Xiaodong Wang

Int. J. Mol. Sci. 2022, 23(11), 6343; https://doi.org/10.3390/ijms23116343 - 6 Jun 2022

Cited by 6 | Viewed by 2861

Abstract

Monte Carlo simulations can quantify various types of DNA damage to evaluate the biological effects of ionizing radiation at the nanometer scale. This work presents a study simulating the DNA target response after proton irradiation. A chromatin fiber model and new physics constructors [...] Read more.

Monte Carlo simulations can quantify various types of DNA damage to evaluate the biological effects of ionizing radiation at the nanometer scale. This work presents a study simulating the DNA target response after proton irradiation. A chromatin fiber model and new physics constructors with the ELastic Scattering of Electrons and Positrons by neutral Atoms (ELSEPA) model were used to describe the DNA geometry and the physical stage of water radiolysis with the Geant4-DNA toolkit, respectively. Three key parameters (the energy threshold model for strand breaks, the physics model and the maximum distance to distinguish DSB clusters) of scoring DNA damage were studied to investigate the impact on the uncertainties of DNA damage. On the basis of comparison of our results with experimental data and published findings, we were able to accurately predict the yield of various types of DNA damage. Our results indicated that the difference in physics constructor can cause up to 56.4% in the DNA double-strand break (DSB) yields. The DSB yields were quite sensitive to the energy threshold for strand breaks (SB) and the maximum distance to classify the DSB clusters, which were even more than 100 times and four times than the default configurations, respectively. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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18 pages, 6255 KiB

Open AccessArticle

Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE

by Hans Liew, Stewart Mein, Thomas Tessonnier, Christian P. Karger, Amir Abdollahi, Jürgen Debus, Ivana Dokic and Andrea Mairani

Int. J. Mol. Sci. 2022, 23(11), 6268; https://doi.org/10.3390/ijms23116268 - 3 Jun 2022

Cited by 4 | Viewed by 2194

Abstract

Accurate knowledge of the relative biological effectiveness (RBE) and its dependencies is crucial to support modern ion beam therapy and its further development. However, the influence of different dose rates of the reference radiation and ion beam are rarely considered. The ion beam [...] Read more.

Accurate knowledge of the relative biological effectiveness (RBE) and its dependencies is crucial to support modern ion beam therapy and its further development. However, the influence of different dose rates of the reference radiation and ion beam are rarely considered. The ion beam RBE-model within our “UNIfied and VERSatile bio response Engine” (UNIVERSE) is extended by including DNA damage repair kinetics to investigate the impact of dose-rate effects on the predicted RBE. It was found that dose-rate effects increase with dose and biological effects saturate at high dose-rates, which is consistent with data- and model-based studies in the literature. In a comparison with RBE measurements from a high dose in-vivo study, the predictions of the presented modification were found to be improved in comparison to the previous version of UNIVERSE and existing clinical approaches that disregard dose-rate effects. Consequently, DNA repair kinetics and the different dose rates applied by the reference and ion beams might need to be considered in biophysical models to accurately predict the RBE. Additionally, this study marks an important step in the further development of UNIVERSE, extending its capabilities in giving theoretical guidance to support progress in ion beam therapy. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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17 pages, 1962 KiB

Open AccessArticle

Flying without a Net: Space Radiation Cancer Risk Predictions without a Gamma-ray Basis

by Francis A. Cucinotta

Int. J. Mol. Sci. 2022, 23(8), 4324; https://doi.org/10.3390/ijms23084324 - 13 Apr 2022

Cited by 11 | Viewed by 2405

Abstract

The biological effects of high linear energy transfer (LET) radiation show both a qualitative and quantitative difference when compared to low-LET radiation. However, models used to estimate risks ignore qualitative differences and involve extensive use of gamma-ray data, including low-LET radiation epidemiology, quality [...] Read more.

The biological effects of high linear energy transfer (LET) radiation show both a qualitative and quantitative difference when compared to low-LET radiation. However, models used to estimate risks ignore qualitative differences and involve extensive use of gamma-ray data, including low-LET radiation epidemiology, quality factors (QF), and dose and dose-rate effectiveness factors (DDREF). We consider a risk prediction that avoids gamma-ray data by formulating a track structure model of excess relative risk (ERR) with parameters estimated from animal studies using high-LET radiation. The ERR model is applied with U.S. population cancer data to predict lifetime risks to astronauts. Results for male liver and female breast cancer risk show that the ERR model agrees fairly well with estimates of a QF model on non-targeted effects (NTE) and is about 2-fold higher than the QF model that ignores NTE. For male or female lung cancer risk, the ERR model predicts about a 3-fold and more than 7-fold lower risk compared to the QF models with or without NTE, respectively. We suggest a relative risk approach coupled with improved models of tissue-specific cancers should be pursued to reduce uncertainties in space radiation risk projections. This approach would avoid low-LET uncertainties, while including qualitive effects specific to high-LET radiation. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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15 pages, 2716 KiB

Open AccessArticle

Nanodosimetric Calculations of Radiation-Induced DNA Damage in a New Nucleus Geometrical Model Based on the Isochore Theory

by Yann Thibaut, Nicolas Tang, Hoang Ngoc Tran, Aurélie Vaurijoux, Carmen Villagrasa, Sébastien Incerti and Yann Perrot

Int. J. Mol. Sci. 2022, 23(7), 3770; https://doi.org/10.3390/ijms23073770 - 29 Mar 2022

Cited by 8 | Viewed by 2545

Abstract

Double-strand breaks (DSBs) in nuclear DNA represents radiation-induced damage that has been identified as particularly deleterious. Calculating this damage using Monte Carlo track structure modeling could be a suitable indicator to better assess and anticipate the side-effects of radiation therapy. However, as already [...] Read more.

Double-strand breaks (DSBs) in nuclear DNA represents radiation-induced damage that has been identified as particularly deleterious. Calculating this damage using Monte Carlo track structure modeling could be a suitable indicator to better assess and anticipate the side-effects of radiation therapy. However, as already demonstrated in previous work, the geometrical description of the nucleus and the DNA content used in the simulation significantly influence damage calculations. Therefore, in order to obtain accurate results, this geometry must be as realistic as possible. In this study, a new geometrical model of an endothelial cell nucleus and DNA distribution according to the isochore theory are presented and used in a Monte Carlo simulation chain based on the Geant4-DNA toolkit. In this theory, heterochromatin and euchromatin compaction are distributed along the genome according to five different families (L1, L2, H1, H2, and H3). Each of these families is associated with a different hetero/euchromatin rate related to its compaction level. In order to compare the results with those obtained using a previous nuclear geometry, simulations were performed for protons with linear energy transfers (LETs) of 4.29 keV/µm, 19.51 keV/µm, and 43.25 keV/µm. The organization of the chromatin fibers at different compaction levels linked to isochore families increased the DSB yield by 6–10%, and it allowed the most affected part of the genome to be identified. These new results indicate that the genome core is more radiosensitive than the genome desert, with a 3–8% increase in damage depending on the LET. This work highlights the importance of using realistic distributions of chromatin compaction levels to calculate radio-induced damage using Monte Carlo simulation methods. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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12 pages, 2320 KiB

Open AccessArticle

Healthy Tissue Damage Following Cancer Ion Therapy: A Radiobiological Database Predicting Lymphocyte Chromosome Aberrations Based on the BIANCA Biophysical Model

by Alessia Embriaco, Ricardo Ramos, Mario Carante, Alfredo Ferrari, Paola Sala, Valerio Vercesi and Francesca Ballarini

Int. J. Mol. Sci. 2021, 22(19), 10877; https://doi.org/10.3390/ijms221910877 - 8 Oct 2021

Cited by 8 | Viewed by 2181

Abstract

Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor [...] Read more.

Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor of radiotherapy total dose. In this framework, a radiobiological database describing the induction of PBL dicentrics as a function of ion type and energy was developed by means of the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model, which has been previously applied to predict the effectiveness of therapeutic-like ion beams at killing tumour cells. This database was then read by the FLUKA Monte Carlo transport code, thus allowing us to calculate the Relative Biological Effectiveness (RBE) for dicentric induction along therapeutic C-ion beams. A comparison with previous results showed that, while in the higher-dose regions (e.g., the Spread-Out Bragg Peak, SOBP), the RBE for dicentrics was lower than that for cell survival. In the lower-dose regions (e.g., the fragmentation tail), the opposite trend was observed. This work suggests that, at least for some irradiation scenarios, calculating the biological effectiveness of a hadrontherapy beam solely based on the RBE for cell survival may lead to an underestimation of the risk of (late) damage to healthy tissues. More generally, following this work, BIANCA has gained the capability of providing RBE predictions not only for cell killing, but also for healthy tissue damage. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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Review

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23 pages, 3325 KiB

Open AccessReview

New Facets of DNA Double Strand Break Repair: Radiation Dose as Key Determinant of HR versus c-NHEJ Engagement

by Emil Mladenov, Veronika Mladenova, Martin Stuschke and George Iliakis

Int. J. Mol. Sci. 2023, 24(19), 14956; https://doi.org/10.3390/ijms241914956 - 6 Oct 2023

Cited by 5 | Viewed by 3538

Abstract

Radiation therapy is an essential component of present-day cancer management, utilizing ionizing radiation (IR) of different modalities to mitigate cancer progression. IR functions by generating ionizations in cells that induce a plethora of DNA lesions. The most detrimental among them are the DNA [...] Read more.

Radiation therapy is an essential component of present-day cancer management, utilizing ionizing radiation (IR) of different modalities to mitigate cancer progression. IR functions by generating ionizations in cells that induce a plethora of DNA lesions. The most detrimental among them are the DNA double strand breaks (DSBs). In the course of evolution, cells of higher eukaryotes have evolved four major DSB repair pathways: classical non-homologous end joining (c-NHEJ), homologous recombination (HR), alternative end-joining (alt-EJ), and single strand annealing (SSA). These mechanistically distinct repair pathways have different cell cycle- and homology-dependencies but, surprisingly, they operate with widely different fidelity and kinetics and therefore contribute unequally to cell survival and genome maintenance. It is therefore reasonable to anticipate tight regulation and coordination in the engagement of these DSB repair pathway to achieve the maximum possible genomic stability. Here, we provide a state-of-the-art review of the accumulated knowledge on the molecular mechanisms underpinning these repair pathways, with emphasis on c-NHEJ and HR. We discuss factors and processes that have recently come to the fore. We outline mechanisms steering DSB repair pathway choice throughout the cell cycle, and highlight the critical role of DNA end resection in this process. Most importantly, however, we point out the strong preference for HR at low DSB loads, and thus low IR doses, for cells irradiated in the G₂-phase of the cell cycle. We further explore the molecular underpinnings of transitions from high fidelity to low fidelity error-prone repair pathways and analyze the coordination and consequences of this transition on cell viability and genomic stability. Finally, we elaborate on how these advances may help in the development of improved cancer treatment protocols in radiation therapy. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 2.0)

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