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 Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

2018 ◽  
Vol 19 (8) ◽  
pp. 2389 ◽  
Author(s):  
Md. Hossain ◽  
Yunfeng Lin ◽  
Shan Yan
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Strand Break ◽  
Single Strand ◽  
Genome Integrity ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response ◽  
End Resection

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

scholarly journals APE2 promotes DNA damage response pathway from a single-strand break

2018 ◽  
Vol 46 (5) ◽  
pp. 2479-2494 ◽  
Author(s):  
Yunfeng Lin ◽  
Liping Bai ◽  
Steven Cupello ◽  
Md Akram Hossain ◽  
Bradley Deem ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Damage Response ◽  
Dna Damage Response Pathway

Abstract 15981: DNA Single-strand Break-induced DNA Damage Response Causes Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Tomoaki Higo ◽  
Atsuhiko Naito ◽  
Masato Shibamoto ◽  
Jong-Kook Lee ◽  
Shungo Hikoso ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dna Damage ◽  
Inflammatory Cytokines ◽  
Dna Damage Response ◽  
Nuclear Translocation ◽  
Pressure Overload ◽  
Strand Break ◽  
Single Strand Break ◽  
Failing Heart ◽  
Damage Response

Introduction: The DNA damage response (DDR) pathway is activated upon DNA damage. In mitotic cells, the DDR plays essential role in maintaining genomic stability and preventing cancer formation. DNA damage and activation of the DDR are also observed in the post-mitotic cardiomyocytes of patients with end-stage heart failure, however, their roles in the pathogenesis of heart failure remains elusive. Methods and Results: We performed transverse aortic constriction (TAC) operation to produce mice model of pressure-overload induced heart failure. Alkaline- and neutral- comet assay revealed that unrepaired DNA single-strand break (SSB), not double-strand break, is accumulated in cardiomyocytes of the failing heart. Mice with cardiomyocyte-specific deletion of XRCC1, a scaffold protein essential for SSB repair, exhibited more severe heart failure and higher mortality after TAC operation. Knockdown of Xrcc1 using siRNA produced SSB accumulation in cardiomyocytes and SSB accumulation induced persistent DDR through activation of ataxia telangiectasia mutated (ATM) kinase. Activated ATM also induced nuclear translocation of NF-κB and increased the expression of inflammatory cytokines. Activation of DDR, nuclear translocation of NF-κB, and increased expression of inflammatory cytokines were also observed in the failing heart and were enhanced in the heart of cardiomyocyte-specific XRCC1 knockout mice. Conclusions: Unrepaired DNA SSB accumulates in post-mitotic cardiomyocytes and plays a pathogenic role in pressure overload-induced heart failure. Approaches that promote efficient SSB repair or suppress aberrant activation of DDR pathway may become a novel therapeutic strategy against heart failure.

Motor Coordination in Space: An Analysis of the Effects of Microgravity on XRCCI DNA Repair Protein Function

2020 ◽  
Author(s):  
Vishruth Nagam
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein Function ◽  
Motor Coordination ◽  
Strand Break ◽  
Single Strand Break ◽  
Single Strand Break Repair ◽  
Repair Protein ◽  
Mature Neurons ◽  
Microgravity Conditions

Abstract While in space, astronauts have been known to face exposure to stressors that may increase susceptibility to DNA damage. If DNA repair proteins are defective or nonexistent, DNA mutations may accumulate, causing increasingly abnormal function as one ages [1]. The DNA single-strand break repair protein XRCC1 is important for cerebellar neurogenesis and interneuron development [2]. According to previous studies, a deficiency of XRCC1 can lead to an increase in DNA damage, in mature neurons, and ataxia (a progressive loss of motor coordination) [2]. I propose to address how XRCC1’s efficiency can change in microgravity conditions. This experiment’s relevance is underscored by the importance of motor coordination and physical fitness for astronauts; determining the potential effects of microgravity on XRCC1 is crucial for future space exploration.

scholarly journals Proton transport modeling in a realistic biological environment by using TILDA-V

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mario E. Alcocer-Ávila ◽  
Michele A. Quinto ◽  
Juan M. Monti ◽  
Roberto D. Rivarola ◽  
Christophe Champion
Keyword(s):  
Monte Carlo ◽  
Dna Lesions ◽  
Track Structure ◽  
Living Matter ◽  
Slowing Down ◽  
Cellular Environment ◽  
Realistic Description ◽  
Radiation Induced ◽  
Biological Environment ◽  
Nanoscale Level

Abstract Whether it is in radiobiology to identify DNA lesions or in medicine to adapt the radiotherapeutic protocols, a detailed understanding of the radiation-induced interactions in living matter is required. Monte Carlo track-structure codes have been successfully developed to describe these interactions and predict the radiation-induced energy deposits at the nanoscale level in the medium of interest. In this work, the quantum-mechanically based Monte Carlo track-structure code TILDA-V has been used to compute the slowing-down of protons in water and DNA. Stopping power and range are then reported and compared with existing data. Then, a first application of TILDA-V to cellular irradiations is also reported in order to highlight the absolute necessity of taking into account a realistic description of the cellular environment in microdosimetry.

scholarly journals APE2 Zf-GRF facilitates 3′-5′ resection of DNA damage following oxidative stress

2016 ◽  
Vol 114 (2) ◽  
pp. 304-309 ◽  
Author(s):  
Bret D. Wallace ◽  
Zachary Berman ◽  
Geoffrey A. Mueller ◽  
Yunfeng Lin ◽  
Timothy Chang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Nucleic Acid ◽  
Oxidative Dna Damage ◽  
Strand Break ◽  
Binding Activity ◽  
Nucleic Acid Binding ◽  
Catalytic Core ◽  
Single Strand Break ◽  
X Ray

The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3′-5′ nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3α (TOP3α) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X-ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/exonuclease/phosphatase (EEP) catalytic core. Structure-guided Zf-GRF mutations impact APE2 DNA binding and 3′-5′ exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9.

Quantitative modelling of DNA damage using Monte Carlo track structure method

1999 ◽  
Vol 38 (1) ◽  
pp. 31-38 ◽  
Author(s):  
H. Nikjoo ◽  
P. O'Neill ◽  
M. Terrissol ◽  
D. T. Goodhead
Keyword(s):  
Dna Damage ◽  
Monte Carlo ◽  
Track Structure ◽  
Quantitative Modelling

scholarly journals Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2

2010 ◽  
Vol 190 (3) ◽  
pp. 297-305 ◽  
Author(s):  
Naihan Xu ◽  
Nadia Hegarat ◽  
Elizabeth J. Black ◽  
Mary T. Scott ◽  
Helfrid Hochegger ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein A ◽  
Strand Break ◽  
Checkpoint Activation ◽  
Interacting Protein ◽  
Dna Double Strand Break ◽  
Radiation Induced ◽  
G2 Cells ◽  
Tumor Types

Using chemical genetics to reversibly inhibit Cdk1, we find that cells arrested in late G2 are unable to delay mitotic entry after irradiation. Late G2 cells detect DNA damage lesions and form γ-H2AX foci but fail to activate Chk1. This reflects a lack of DNA double-strand break processing because late G2 cells fail to recruit RPA (replication protein A), ATR (ataxia telangiectasia and Rad3 related), Rad51, or CtIP (C-terminal interacting protein) to sites of radiation-induced damage, events essential for both checkpoint activation and initiation of DNA repair by homologous recombination. Remarkably, inhibition of Akt/PKB (protein kinase B) restores DNA damage processing and Chk1 activation after irradiation in late G2. These data demonstrate a previously unrecognized role for Akt in cell cycle regulation of DNA repair and checkpoint activation. Because Akt/PKB is frequently activated in many tumor types, these findings have important implications for the evolution and therapy of such cancers.

The complex matter of DNA double-strand break detection

2003 ◽  
Vol 31 (1) ◽  
pp. 40-44 ◽  
Author(s):  
J.M. Bradbury ◽  
S.P. Jackson
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Strand Break ◽  
Damage Sensing ◽  
Dna Double Strand Break ◽  
Mre11 Complex ◽  
Damage Response ◽  
Radiation Induced ◽  
Dna Damage Signalling ◽  
Complex Matter

To maintain genomic stability, despite constant exposure to agents that damage DNA, eukaryotic cells have developed elaborate and highly conserved pathways of DNA damage sensing, signalling and repair. In this review, we concentrate mainly on what we know about DNA damage sensing with particular reference to Lcd1p, a yeast protein that functions early in DNA damage signalling, and MDC1 (mediator of DNA damage checkpoint 1), a recently identified human protein that may be involved in recruiting the MRE11 complex to radiation-induced nuclear foci. We describe a model for the DNA damage response in which factors are recruited sequentially to sites of DNA damage to form complexes that can amplify the original signal and propagate it to the multitude of response pathways necessary for genome stability.

scholarly journals Metal Ions Modify in Vitro DNA Damage Yields With High-LET Radiation

2021 ◽  
Author(s):  
Dylan Buglewicz ◽  
Cathy Su ◽  
Austin Banks ◽  
Jazmine Strenger-smith ◽  
Suad Elmegerhi ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Strand Break ◽  
Single Strand ◽  
Iron Ion ◽  
Single Strand Break ◽  
Carbon Ion ◽  
X Ray ◽  
High Let ◽  
Break Formation

Abstract Cu2+ and Co2+ are metals known to increase DNA damage in the presence of hydrogen peroxide through a Fenton type reaction. We hypothesized that these metals could increase DNA damage following irradiations of increasing LET values as hydrogen peroxide is a product of the radiolysis of water. The reaction mixtures contain either double- or single-stranded DNA in solution with Cu2+ or Co2+ and was irradiated either with X-ray, carbon-ion or iron-ion beams or was treated with hydrogen peroxide or bleomycin at increasing radiation dosages or chemical concentrations. DNA damage was then assessed by gel electrophoresis followed by band intensity analysis. DNA in solution with metals demonstrated the most DNA damage when treated with hydrogen peroxide followed by irradiation with low-LET (X-Ray), high-LET (carbon-ion and iron-ion), respectively, and demonstrated the least damage with treatment of bleomycin. Cu2+ portrayed greater DNA damage than Co2+ following all experimental conditions. The metals effect caused more DNA damage and was observed to be LET dependent for single-strand break formation but inversely dependent for double-strand break formation. These results suggest that Cu2+ is more efficient than Co2+ at inducing both DNA single-strand and double-strand breaks following all irradiations and chemical treatments.

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