Interspecies Differences in the Removal of DNA Adducts

1983 ◽  
Vol 2 (1) ◽  
pp. 7-17 ◽  
Author(s):  
Ronald W. Hart ◽  
Ming J.W. Chang
Keyword(s):  
Dna Damage ◽  
Birth Defects ◽  
Dna Adducts ◽  
Repair Process ◽  
Information Redundancy ◽  
Chemical Agents ◽  
Post Replication Repair ◽  
Cellular Dna ◽  
Physical And Chemical

Numerous physical and chemical agents damage cellular DNA in vivo. Such damage has been associated with various biochemical, physiological, and pathological dysfunctions including: alterations in gene expression, cell death, mutation, birth defects, cancer, and aging. Cells and organisms unable to prevent the induction of DNA damage or to repair such damage once it is induced, are predisposed to one or more of these pathologies. Over the course of evolution, living systems have developed various mechanisms to cope with such damage including enzymatic repair, information redundancy and, in extreme situations, cellular replacement. Enzymatic repair can be divided into two general categories: prereplication and post-replication repair. Each of these categories includes many “repair” systems which differ with the size of the repaired region, the nature of the enzymes involved in the repair process, the type of agent inducing the repair process or form of lesion removed. Over the last decade, numerous methods have been developed to measure DNA damage, both directly as well as indirectly, but few studies exist comparing the results of these methods with one another. Little is known as to whether these methods are measuring the same or different endpoints. Interspecies, intertissue, and interorgan comparisons can only be made when comparable techniques have been utilized. From such studies, it is now apparent that significant differences in DNA repair exist among species, within species, and between organs. Further, it is now a reasonable speculation that such differences may, in part, account for differences in organ susceptibility and risk per cell per unit time for spontaneous malignant transformation observed between species.

scholarly journals Targeting Cellular DNA Damage Responses in Cancer: An In Vitro-Calibrated Agent-Based Model Simulating Monolayer and Spheroid Treatment Responses to ATR-Inhibiting Drugs

2021 ◽  
Vol 83 (10) ◽  
Author(s):  
Sara Hamis ◽  
James Yates ◽  
Mark A. J. Chaplain ◽  
Gibin G. Powathil
Keyword(s):  
Dna Damage ◽  
Drug Development ◽  
Agent Based Model ◽  
Agent Based ◽  
Preclinical Drug Development ◽  
Dna Damage Responses ◽  
Treatment Responses ◽  
Cellular Dna

AbstractWe combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia–telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.

Ectopic recombination between Ty elements in Saccharomyces cerevisiae is not induced by DNA damage

1992 ◽  
Vol 12 (10) ◽  
pp. 4441-4448
Author(s):  
A Parket ◽  
M Kupiec
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Uv Irradiation ◽  
Mitotic Recombination ◽  
Methyl Methanesulfonate ◽  
Ectopic Recombination ◽  
Ty Elements ◽  
Chemical Agents ◽  
Physical And Chemical

Mitotic recombination is increased when cells are treated with a variety of physical and chemical agents that cause damage to their DNA. We show here, using Saccharomyces cerevisiae strains that carry marked Ty elements, that recombination between members of this family of retrotransposons is not increased by UV irradiation or by treatment with the radiomimetic drug methyl methanesulfonate. Both ectopic recombination and mutation events were elevated by these agents for non-Ty sequences in the same strain. We discuss possible mechanisms that can prevent the induction of recombination between Ty elements.

Measurement of Individual p53-Specific Damage Formation and Repair Following In Vitro Exposure of Peripheral Mononuclear Cells to Melphalan May Predict Clinical Outcome in Patients with Multiple Myeloma (MM) Subsequently Treated with High Dose Melphalan (HDM) and Autologous Blood Stem Cell Transplantation (ASCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1167-1167
Author(s):  
Meletios A. Dimopoulos ◽  
V. L. Souliotis ◽  
A. Anagnostopoulos ◽  
A. Pouli ◽  
I. Baltadakis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Clinical Outcome ◽  
Dna Adducts ◽  
P53 Gene ◽  
Peripheral Blood Lymphocytes ◽  
P Value ◽  
In Vitro Measurements ◽  
In Vitro Exposure

Abstract Introduction: Melphalan reacts extensively with cellular DNA. DNA monoadducts (MA) and interstrand cross-links (ICL) are the main events occurring after drug exposure. Subsequently, complex pathways contribute to repair of DNA lesions. We have previously showed that individual repairing capacity in p53 gene in vivo varied up to 16-fold among pts with MM receiving HDM, while increased DNA damage and slower repairing capacity correlated with improved clinical outcome (Dimopoulos et al, JCO 2005). We examine here if measurement of gene-specific DNA damage formation and repair after in vitro exposure of peripheral blood lymphocytes (PBL) to melphalan correlates with in vivo DNA damage and repair after exposure to HDM and if in vitro findings correlate with subsequent clinical outcome. Methods: Gene-specific MA and ICL formation and repair in the p53 gene were measured in PBL from MM pts, candidates for HDM (200mg/m2) and ASCT following in vitro exposure to 10 μg/ml melphalan for 1 h at 37°C. Measurements were performed 0, 2, 8 and 24 hours after in vitro exposure to melphalan. The same measurements were performed in vivo at 0, 2, 8 and 24 hours after treatment with HDM as previously described. Individual amounts of each type of DNA adducts over time (0–24h) were assessed by the area under the curve (AUC) during the whole experiment. Response after HDM was assessed according to the EBMT criteria. Measurements of DNA adducts after in vivo and in vitro treatment were correlated by the correlation-coefficient method. Results: So far, in 25 pts in vitro measurements have been performed and in 15 pts in vivo measurements and correlations with clinical outcome were made as well. One pt was treated in relapse, 3 patients had primary refractory disease and 11 were in remission. Individual kinetics of melphalan-induced DNA damage formation and repair varied remarkably among patients both for the in vivo and in vitro measurements. A strong correlation between in vivo and in vitro measurements was found (p≤0.02 for all measurements). Patients were separated into 2 groups. Responders i.e. patients who achieved CR or PR (n=10) after HDM and non responders i.e. pts who were rated as SD or PD (n=5). A significant correlation of clinical response with p53 gene-specific damage formation and repair was found in both in vitro and in vivo data. AUC (adducts/106 nucleotides x h) Total adducts (mean) Interstrand crosslinks (mean) Monoadducts (mean) Responders 919 +/− 215 303,9 +/− 108 616 +/− 154 In vitro Non responders 495 +/− 220 161,3 +/− 80,8 336 +/− 154 p-value 0,003 0,02 0,006 Responders 257 +/− 76 29,4 +/− 8,5 229 +/− 68 In vivo Non responders 122 +/− 91 13,8 +/− 4,6 112,8 +/− 82 p-value 0,009 0,002 0,01 Conclusion: Our results suggests that individuals with slower repairing capacity of the in vitro melphalan-induced p53 damage in peripheral blood lymphocytes have improved clinical outcome following subsequent treatment with HDM. We believe that our ongoing study may help select patients with MM who are more likely to benefit from HDM.

scholarly journals Molecular Spectroscopic Markers of DNA Damage

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 561 ◽  
Author(s):  
Kamila Sofińska ◽  
Natalia Wilkosz ◽  
Marek Szymoński ◽  
Ewelina Lipiec
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
Living Organism ◽  
Eukaryotic Cell ◽  
Dna Lesions ◽  
Spectral Signature ◽  
Dna Solutions ◽  
Using Data ◽  
Cellular Dna ◽  
Physical And Chemical

Every cell in a living organism is constantly exposed to physical and chemical factors which damage the molecular structure of proteins, lipids, and nucleic acids. Cellular DNA lesions are the most dangerous because the genetic information, critical for the identity and function of each eukaryotic cell, is stored in the DNA. In this review, we describe spectroscopic markers of DNA damage, which can be detected by infrared, Raman, surface-enhanced Raman, and tip-enhanced Raman spectroscopies, using data acquired from DNA solutions and mammalian cells. Various physical and chemical DNA damaging factors are taken into consideration, including ionizing and non-ionizing radiation, chemicals, and chemotherapeutic compounds. All major spectral markers of DNA damage are presented in several tables, to give the reader a possibility of fast identification of the spectral signature related to a particular type of DNA damage.

Short‐term “in vivo” study on cellular DNA damage induced by acrylic Andresen activator in oral mucosa cells

2019 ◽  
Vol 22 (3) ◽  
pp. 208-212 ◽  
Author(s):  
Paolo Faccioni ◽  
Daniele De Santis ◽  
Stefano Sinigaglia ◽  
Paola Pancera ◽  
Fiorenzo Faccioni ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oral Mucosa ◽  
In Vivo Study ◽  
Short Term ◽  
Cellular Dna

scholarly journals Comet assay as a method used in research on DNA damage caused by pesticides in fish

2021 ◽  
Vol 77 (01) ◽  
pp. 6482-2021
Author(s):  
Księżarczyk M. ◽  
Leśniak P. ◽  
Arciszewski M. B. ◽  
Valverde Piedra J. L.
Keyword(s):  
Dna Damage ◽  
Comet Assay ◽  
Research Method ◽  
Genetic Material ◽  
Aquatic Organisms ◽  
Assay Method ◽  
Negative Effects ◽  
Chemical Agents ◽  
Harmful Substances ◽  
Cellular Dna

The comet assay method is a research technique for detecting damage to cellular DNA due to active physical or chemical agents. The comet assay is based on electrophoretic migration of genetic material contained in the cell’s nucleus. This research method is commonly used in many different fields, such as toxicology, environmental protection, and pharmacology. In recent years, the comet assay has attracted considerable attention from scientists studying the effects of harmful substances on the genetic material in the cell’s nucleus. The presence of pesticides in the environment is a threat to animals, because of the negative effects of pesticides on cells and their genetic material. Therefore, the aim of this paper, based on the available literature, was to describe the use of the comet assay in assessing the genotoxicity of pesticides to cells of aquatic organisms, as well as to describe the methodology and potential complications of this procedure.

scholarly journals DNA damage and repair process in earthworm after in-vivo and in vitro exposure to soils irrigated by wastewaters

2007 ◽  
Vol 148 (1) ◽  
pp. 141-147 ◽  
Author(s):  
Min Qiao ◽  
Ying Chen ◽  
Chun-Xia Wang ◽  
Zijian Wang ◽  
Yong-Guan Zhu
Keyword(s):  
Dna Damage ◽  
Repair Process ◽  
Dna Damage And Repair ◽  
In Vitro Exposure

scholarly journals BRCA1 Forms a Functional Complex withγ-H2AX as a Late Response to Genotoxic Stress

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Susan A. Krum ◽  
Esther de la Rosa Dalugdugan ◽  
Gustavo A. Miranda-Carboni ◽  
Timothy F. Lane
Keyword(s):  
Dna Damage ◽  
Genotoxic Stress ◽  
Repair Process ◽  
26S Proteasome ◽  
Late Response ◽  
Histone H2ax ◽  
Ubiquitin Ligase Activity ◽  
Functional Complex

Following genotoxic stress, the histone H2AX becomes phosphorylated at serine 139 by the ATM/ATR family of kinases. The tumor suppressor BRCA1, also phosphorylated by ATM/ATR kinases, is one of several proteins that colocalize with phospho-H2AX (γ-H2AX) at sites of active DNA repair. Both the precise mechanism and the purpose of BRCA1 recruitment to sites of DNA damage are unknown. Here we show that BRCA1 andγ-H2AX form an acid-stable biochemical complex on chromatin after DNA damage. Maximal association of BRCA1 withγ-H2AX correlates with reduced globalγ-H2AX levels on chromatin late in the repair process. Since BRCA1 is known to have E3 ubiquitin ligase activityin vitro, we examined H2AX for evidence of ubiquitination. We found that H2AX is ubiquitinated at lysines 119 and 119in vivoand that blockage of 26S proteasome function stabilizesγ-H2AX levels within cells. When BRCA1 levels were reduced, ubiquitination of H2AX was also reduced, and the cells retained higher levels of phosphorylated H2AX. These results indicate that BRCA1 is recruited into stable complexes withγ-H2AX and that the complex is involved in attenuation of theγ-H2AX repair signal after DNA damage.

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