scholarly journals A Geant4-DNA Evaluation of Radiation-Induced DNA Damage on a Human Fibroblast

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4940
Author(s):  
Wook-Geun Shin ◽  
Dousatsu Sakata ◽  
Nathanael Lampe ◽  
Oleg Belov ◽  
Ngoc Hoang Tran ◽  
...  
Keyword(s):  
Dna Damage ◽  
Monte Carlo ◽  
Ionizing Radiation ◽  
Human Fibroblast ◽  
Length Distribution ◽  
Fibroblast Cell ◽  
Strand Break ◽  
Recent Experimental Data ◽  
Water Radiolysis ◽  
Biological Targets

Accurately modeling the radiobiological mechanisms responsible for the induction of DNA damage remains a major scientific challenge, particularly for understanding the effects of low doses of ionizing radiation on living beings, such as the induction of carcinogenesis. A computational approach based on the Monte Carlo technique to simulate track structures in a biological medium is currently the most reliable method for calculating the early effects induced by ionizing radiation on DNA, the primary cellular target of such effects. The Geant4-DNA Monte Carlo toolkit can simulate not only the physical, but also the physico-chemical and chemical stages of water radiolysis. These stages can be combined with simplified geometric models of biological targets, such as DNA, to assess direct and indirect early DNA damage. In this study, DNA damage induced in a human fibroblast cell was evaluated using Geant4-DNA as a function of incident particle type (gammas, protons, and alphas) and energy. The resulting double-strand break yields as a function of linear energy transfer closely reproduced recent experimental data. Other quantities, such as fragment length distribution, scavengeable damage fraction, and time evolution of damage within an analytical repair model also supported the plausibility of predicting DNA damage using Geant4-DNA.The complete simulation chain application “molecularDNA”, an example for users of Geant4-DNA, will soon be distributed through Geant4.

scholarly journals βarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1

2019 ◽  
Vol 27 (4) ◽  
pp. 1200-1213 ◽  
Author(s):  
Ainhoa Nieto ◽  
Makoto R. Hara ◽  
Victor Quereda ◽  
Wayne Grant ◽  
Vanessa Saunders ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Molecular Scaffold ◽  
Strand Breaks

Abstract Cellular DNA is constantly under threat from internal and external insults, consequently multiple pathways have evolved to maintain chromosomal fidelity. Our previous studies revealed that chronic stress, mediated by continuous stimulation of the β2-adrenergic-βarrestin-1 signaling axis suppresses activity of the tumor suppressor p53 and impairs genomic integrity. In this pathway, βarrestin-1 (βarr1) acts as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, MDM2. We sought to determine whether βarr1 plays additional roles in the repair of DNA damage. Here we demonstrate that in mice βarr1 interacts with p53-binding protein 1 (53BP1) with major consequences for the repair of DNA double-strand breaks. 53BP1 is a principle component of the DNA damage response, and when recruited to the site of double-strand breaks in DNA, 53BP1 plays an important role coordinating repair of these toxic lesions. Here, we report that βarr1 directs 53BP1 degradation by acting as a scaffold for the E3-ubiquitin ligase Rad18. Consequently, knockdown of βarr1 stabilizes 53BP1 augmenting the number of 53BP1 DNA damage repair foci following exposure to ionizing radiation. Accordingly, βarr1 loss leads to a marked increase in irradiation resistance both in cells and in vivo. Thus, βarr1 is an important regulator of double strand break repair, and disruption of the βarr1/53BP1 interaction offers an attractive strategy to protect cells against high levels of exposure to ionizing radiation.

scholarly journals Fully integrated Monte Carlo simulation for evaluating radiation induced DNA damage and subsequent repair using Geant4-DNA

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Dousatsu Sakata ◽  
Oleg Belov ◽  
Marie-Claude Bordage ◽  
Dimitris Emfietzoglou ◽  
Susanna Guatelli ◽  
...  
Keyword(s):  
Experimental Data ◽  
Dna Damage ◽  
Monte Carlo ◽  
Biological Response ◽  
Strand Break ◽  
Track Structure ◽  
Single Strand Break ◽  
Fully Integrated ◽  
Biological Responses ◽  
Radiation Induced

AbstractIonising radiation induced DNA damage and subsequent biological responses to it depend on the radiation’s track-structure and its energy loss distribution pattern. To investigate the underlying biological mechanisms involved in such complex system, there is need of predicting biological response by integrated Monte Carlo (MC) simulations across physics, chemistry and biology. Hence, in this work, we have developed an application using the open source Geant4-DNA toolkit to propose a realistic “fully integrated” MC simulation to calculate both early DNA damage and subsequent biological responses with time. We had previously developed an application allowing simulations of radiation induced early DNA damage on a naked cell nucleus model. In the new version presented in this work, we have developed three additional important features: (1) modeling of a realistic cell geometry, (2) inclusion of a biological repair model, (3) refinement of DNA damage parameters for direct damage and indirect damage scoring. The simulation results are validated with experimental data in terms of Single Strand Break (SSB) yields for plasmid and Double Strand Break (DSB) yields for plasmid/human cell. In addition, the yields of indirect DSBs are compatible with the experimental scavengeable damage fraction. The simulation application also demonstrates agreement with experimental data of $$\gamma$$ γ -H2AX yields for gamma ray irradiation. Using this application, it is now possible to predict biological response along time through track-structure MC simulations.

scholarly journals Ionizing Radiation and Complex DNA Damage: Quantifying the Radiobiological Damage Using Monte Carlo Simulations

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 799 ◽  
Author(s):  
Konstantinos P. Chatzipapas ◽  
Panagiotis Papadimitroulas ◽  
Dimitris Emfietzoglou ◽  
Spyridon A. Kalospyros ◽  
Megumi Hada ◽  
...  
Keyword(s):  
Dna Damage ◽  
Monte Carlo ◽  
Ionizing Radiation ◽  
Monte Carlo Simulations ◽  
High Energy ◽  
Radiation Biology ◽  
Medical Procedures ◽  
Promising Tool ◽  
Need To Evaluate ◽  
Mc Simulation

Ionizing radiation is a common tool in medical procedures. Monte Carlo (MC) techniques are widely used when dosimetry is the matter of investigation. The scientific community has invested, over the last 20 years, a lot of effort into improving the knowledge of radiation biology. The present article aims to summarize the understanding of the field of DNA damage response (DDR) to ionizing radiation by providing an overview on MC simulation studies that try to explain several aspects of radiation biology. The need for accurate techniques for the quantification of DNA damage is crucial, as it becomes a clinical need to evaluate the outcome of various applications including both low- and high-energy radiation medical procedures. Understanding DNA repair processes would improve radiation therapy procedures. Monte Carlo simulations are a promising tool in radiobiology studies, as there are clear prospects for more advanced tools that could be used in multidisciplinary studies, in the fields of physics, medicine, biology and chemistry. Still, lot of effort is needed to evolve MC simulation tools and apply them in multiscale studies starting from small DNA segments and reaching a population of cells.

scholarly journals Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2012 ◽  
Author(s):  
Clara Dobler ◽  
Tina Jost ◽  
Markus Hecht ◽  
Rainer Fietkau ◽  
Luitpold Distel
Keyword(s):  
Dna Damage ◽  
Squamous Cell Carcinoma ◽  
Ionizing Radiation ◽  
Tumor Cell ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Fibroblast Cell ◽  
Hpv Status ◽  
Damage Response

DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 (ATR; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and ATR inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction.

scholarly journals EPCO-15. TUMOR TREATMENT WITH IONIZING RADIATION IS ASSOCIATED WITH A CLINICALLY RELEVANT DELETION SIGNATURE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii72-ii72
Author(s):  
Emre Kocakavuk ◽  
Kevin Anderson ◽  
Kevin Johnson ◽  
Frederick Varn ◽  
Samirkumar Amin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Radiation Therapy ◽  
Ionizing Radiation ◽  
Cox Regression ◽  
Strand Break ◽  
Rank Test ◽  
Sequencing Data ◽  
End Joining ◽  
Signed Rank Test ◽  
Non Homologous End Joining

Abstract Diffuse gliomas are highly aggressive brain tumors that invariably relapse despite treatment with chemo- and radiotherapy. Treatment with alkylating chemotherapy can drive tumors to develop a hypermutator phenotype. In contrast, the genomic effects of radiation therapy (RT) remain unknown. We analyzed the mutational spectra following treatment with ionizing radiation in sequencing data from 190 paired primary-recurrent gliomas from the Glioma Longitudinal Analysis (GLASS) dataset and 2249 post-treatment metastatic tumors from the Hartwig Medical Foundation. We identified a significant increase in the frequency of small deletions following radiation therapy that was independent of other factors. These novel deletions demonstrated distinct characteristics when compared to pre-existing deletions present prior to RT-treatment and deletions in RT-untreated tumors. Radiation therapy-acquired deletions were characterized by a larger deletion size (GLASS and metastatic cohort, P = 1.2e-02 and P = 8e-11, respectively; Mann-Whitney U test), an increased distance to repetitive DNA elements (P < 2.2e-16, Kolmogorov-Smirnov test) and a reduction in microhomology at breakpoints (P = 3.2e-02, paired Wilcoxon signed-rank test). These observations suggested that canonical non-homologous end joining (c-NHEJ) was the preferred pathway for DNA double strand break repair of RT-induced DNA damage. Furthermore, radiotherapy resulted in frequent chromosomal deletions and significantly increased frequencies of CDKN2A homozygous deletions. Finally, a high burden of RT-associated deletions was associated with worse clinical outcomes (GLASS and metastatic cohort, P = 4.7e-02, HR = 2.59 [95% CI: 1.01, 6.60] and P = 2.5e-02, HR = 1.43 [95% CI: 1.05, 1.94], respectively; multivariable Cox regression), suggesting that effective repair of RT-induced DNA damage is detrimental to patient survival and that inhibiting c-NHEJ may be a viable strategy for improving the cancer-killing effect of radiotherapy. Taken together, the identified genomic scars as a result of radiation therapy reflect a more aggressive tumor with increased levels of resistance to follow up treatments.

Development of cell and protein scale dosimetry tools, and their applications for the optimization of therapeutic protocols using Monte Carlo simulations

2021 ◽  
Author(s):  
Κωνσταντίνος Χατζηπαπάς
Keyword(s):  
Dna Damage ◽  
Monte Carlo ◽  
Ionizing Radiation ◽  
Monte Carlo Simulations ◽  
Dna Damage Response ◽  
Damage Response ◽  
Therapeutic Protocols

Η παρούσα διδακτορική μελέτη, με τίτλο «Ανάπτυξη εργαλείων δοσιμετρίας σε κυτταρικό και πρωτεϊνικό επίπεδο και εφαρμογή τους για τη βελτιστοποίηση θεραπευτικών πρωτοκόλλων με τη χρήση προσομοιώσεων Monte Carlo», είχε ως στόχο την ανάπτυξη ενός εργαλείου υπολογισμού που θα έχει την ικανότητα να εκτιμά την απόκριση του DNA σε βλάβες (DDR) που δημιουργούνται όταν ιονίζουσα ακτινοβολία (IR) αλληλεπιδρά με τη έμβια ύλη. Αυτό το υπολογιστικό εργαλείο στοχεύει στη χρήση του σε κλινικές εφαρμογές είτε για προσομοιώσεις είτε για τη χρήση δεδομένων που έχουν παραχθεί από τη χρήση του. Απώτερος στόχος είναι η βελτιστοποίηση και η εξατομίκευση θεραπευτικών και απεικονιστικών κλινικών πρωτοκόλλων.Η διατριβή έχει οργανωθεί σε 5 κεφάλαια, για την εύκολη κατανόηση του συνόλου της μελέτης. Στο πρώτο κεφάλαιο συζητούνται κάποιες γενικές εισαγωγικές θεωρητικές έννοιες σχετικά με τον τομέα της ραδιοβιολογίας και τη χρησιμότητα της μικρο- και νανο-δοσιμετρίας. Παρουσιάζονται επίσης οι δημοσιεύσεις που εκπονήθηκαν κατά τη διάρκεια αυτής της διδακτορικής διατριβής (ΔΔ). Το δεύτερο κεφάλαιο αποτελεί μια αναλυτική ανασκόπηση των μελετών που έχουν διερευνήσει διάφορες πτυχές των διαδικασιών προσομοίωσης σχετικά με τον ποσοτικό προσδιορισμό της βλάβης του DNA από την ιονίζουσα ακτινοβολία. Οι κώδικες περιγραφής των τροχιών που ακολουθούνται από στοιχειώδη σωμάτια συζητούνται εκτενώς σε αυτό το κεφάλαιο. Επιπλέον, διάφορες τεχνικές σχετικά με το σχεδιασμό τρισδιάστατων μοντέλων μορίων DNA, καθώς και τεχνικές αποκατάστασης της βλάβης του DNA συζητούνται επίσης σε αυτό το κεφάλαιο.Το τρίτο κεφάλαιο περιγράφει μια νέα τεχνική που αναπτύχθηκε στο πλαίσιο αυτής της μελέτης. Αυτή η τεχνική περιλαμβάνει τη χρήση ενός πρωτοτύπου DNA δοσιμέτρου, το οποίο χρησιμοποιήθηκε για τον ποσοτικό προσδιορισμό των σημείων διπλής διάσπασης της έλικας του DNA (DSB), όταν γραμμικά μόρια DNA ακτινοβολούνται από ένα κλινικό γραμμικό επιταχυντή (LINAC). Αυτή η πειραματική διαδικασία στη συνέχεια μοντελοποιήθηκε και προσομοιώθηκε στο Geant4-DNA. Αυτή η διαδικασία επικυρώθηκε και παράλληλα αναπτύχθηκε ένα μαθηματικό μοντέλο, το οποίο μπορεί να χρησιμοποιηθεί για να συσχετίσει τη δόση με τον αριθμό των DNA DSB.Το τέταρτο κεφάλαιο περιγράφει την πλατφόρμα προσομοίωσης που αναπτύχθηκε στο πλαίσιο της παρούσας διδακτορικής εργασίας. Το IDDRRA (DNA Damage Response to Ionizing RAdiation) είναι μια εργαλειοθήκη που αναπτύχθηκε για να χρησιμοποιηθεί στην κλινική πράξη, για τον ποσοτικό προσδιορισμό της DDR. Το IDDRRA περιλαμβάνει εξειδικευμένα εργαλεία για το σχεδιασμό τρισδιάστατων μορίων DNA, την προσομοίωση της ακτινοβόλησης τέτοιων μοντέλων, καθώς και τη διαδικασία ανάλυσης των παραγόμενων αποτελεσμάτων. Κάθε εργαλείο που περιέχεται στο IDDRRA έχει αναπτυχθεί ειδικά για χρήση μέσω της πλατφόρμας, αλλά μπορεί επίσης να χρησιμοποιηθεί ξεχωριστά.Το πέμπτο και τελευταίο κεφάλαιο αυτής της ΔΔ συζητά τα αποτέλεσμα της μελέτης, στο σύνολό τους, καθώς και προοπτικές για μελλοντικούς ερευνητές στον τομέα. Παρατηρείται, ότι η μελέτη της DDR είναι ένα ενεργό πεδίο έρευνας, καθώς εκτός από τις κλινικές εφαρμογές, πολλές μελέτες έχουν επικεντρωθεί στην ποσοτικοποίηση της βλάβης που προκαλείται στους αστροναύτες κατά τη διάρκεια των ταξιδιών στο διάστημα, καθώς και στο γενικό πληθυσμό που έχει πρόσφατα εμπλακεί σε τέτοιου είδους ταξίδια.

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