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

The impact of in vivo and in vitro exposure to base analogue 5-FU on the level of DNA damage in haemocytes of freshwater mussels Unio pictorum and Unio tumidus

2014 ◽  
Vol 191 ◽  
pp. 145-150 ◽  
Author(s):  
Zoran Gačić ◽  
Stoimir Kolarević ◽  
Karolina Sunjog ◽  
Margareta Kračun-Kolarević ◽  
Momir Paunović ◽  
...  
Keyword(s):  
Dna Damage ◽  
Freshwater Mussels ◽  
In Vitro Exposure ◽  
Unio Tumidus ◽  
The Impact ◽  
Unio Pictorum

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 Cisplatin-DNA damage and repair in peripheral blood leukocytes in vivo and in vitro.

1992 ◽  
Vol 98 ◽  
pp. 53-59 ◽  
Author(s):  
M Dabholkar ◽  
L Bradshaw ◽  
R J Parker ◽  
I Gill ◽  
F Bostick-Bruton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Peripheral Blood ◽  
Peripheral Blood Leukocytes ◽  
Blood Leukocytes ◽  
Dna Damage And Repair

scholarly journals Machine Learning-based Biomarkers Identification and Validation from Toxicogenomics - Bridging to Regulatory Relevant Phenotypic Endpoints

2020 ◽  
Author(s):  
Sheikh Mokhlesur Rahman ◽  
Jiaqi Lan ◽  
David Kaeli ◽  
Jennifer Dy ◽  
Akram Alshawabkeh ◽  
...  
Keyword(s):  
Machine Learning ◽  
Dna Damage ◽  
Excision Repair ◽  
Dna Recombination ◽  
In Vitro Assays ◽  
Adverse Outcome Pathway ◽  
Dna Damage And Repair ◽  
Repair Pathways

ABSTRACTHigh-throughput in vitro assays and AOP-based approach is promising for the assessment of health and ecotoxicological risks from exposure to pollutants and their mixtures. However, one of the major challenges in realization and implementations of the Tox21 vision is the urgent need to establish quantitative link between in-vitro assay molecular endpoint and in-vivo phenotypic toxicity endpoint. Here, we demonstrated that, using time series toxicomics in-vitro assay along with machine learning-based feature selection (MRMR) and classification method (SVM), an “optimal” number of biomarkers with minimum redundancy can be identified for prediction of phenotypic endpoints with good accuracy. We included two case studies for in-vivo carcinogenicity and Ames genotoxicity prediction with 20 selected chemicals including model genotoxic chemicals and negative controls, respectively, using an in-vitro toxicogenomic assay that captures real-time proteomic response data of 38 GFP-fused proteins of S. cerevisiae strains covering biomarkers indicative of all known DNA damage and repair pathways in yeast. The results suggested that, employing the adverse outcome pathway (AOP) concept, molecular endpoints based on a relatively small number of properly selected biomarker-ensemble involved in the conserved DNA-damage and repair pathways among eukaryotes, were able to predict both in-vivo carcinogenicity in rats and Ames genotoxicity endpoints. The specific biomarkers identified are different for the two different phenotypic genotoxicity assays. The top-ranked five biomarkers for the in-vivo carcinogenicity prediction mainly focused on double strand break repair and DNA recombination, whereas the selected top-ranked biomarkers for Ames genotoxicity prediction are associated with base- and nucleotide-excision repair. Current toxicomics approach still mostly rely on large number of redundant markers without pre-selection or ranking, therefore, selection of relevant biomarkers with minimal redundancy would reduce the number of markers to be monitored and reduce the cost, time, and complexity of the toxicity screening and risk monitoring. The method developed in this study will help to fill in the knowledge gap in phenotypic anchoring and predictive toxicology, and contribute to the progress in the implementation of tox 21 vision for environmental and health applications.TOC Art

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.

scholarly journals Impact of G-Quadruplexes on the Regulation of Genome Integrity, DNA Damage and Repair

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1284
Author(s):  
Anzhela V. Pavlova ◽  
Elena A. Kubareva ◽  
Mayya V. Monakhova ◽  
Maria I. Zvereva ◽  
Nina G. Dolinnaya
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Critical Role ◽  
Dna Lesions ◽  
Genome Integrity ◽  
Dna Breaks ◽  
Dna Damage And Repair ◽  
Repair Processes

DNA G-quadruplexes (G4s) are known to be an integral part of the complex regulatory systems in both normal and pathological cells. At the same time, the ability of G4s to impede DNA replication plays a critical role in genome integrity. This review summarizes the results of recent studies of G4-mediated genomic and epigenomic instability, together with associated DNA damage and repair processes. Although the underlying mechanisms remain to be elucidated, it is known that, among the proteins that recognize G4 structures, many are linked to DNA repair. We analyzed the possible role of G4s in promoting double-strand DNA breaks, one of the most deleterious DNA lesions, and their repair via error-prone mechanisms. The patterns of G4 damage, with a focus on the introduction of oxidative guanine lesions, as well as their removal from G4 structures by canonical repair pathways, were also discussed together with the effects of G4s on the repair machinery. According to recent findings, there must be a delicate balance between G4-induced genome instability and G4-promoted repair processes. A broad overview of the factors that modulate the stability of G4 structures in vitro and in vivo is also provided here.

scholarly journals De-ubiquitination of SAMHD1 by USP7 overcomes oncogenic stress and contributes to chemotherapy insensitivity

2021 ◽  
Author(s):  
Jingwei Liu ◽  
Tingting Zhou ◽  
xiang dong ◽  
Qiqiang Guo ◽  
Lixia Zheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Viral Infections ◽  
Early Stage ◽  
Genotoxic Stress ◽  
Repair Process ◽  
Chemotherapeutic Agents ◽  
Human Carcinoma ◽  
Oncogenic Stress

Abstract Oncogenic stress induces DNA damage response (DDR) that guards against genetic instability during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression, and promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that targeting USP7 may help overcome chemoresistance, thus necessitating further investigation in the pursuit of precision medicine.

A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage

2019 ◽  
Vol 19 (3) ◽  
pp. 365-374 ◽  
Author(s):  
Yang Liu ◽  
Jingyin Zhang ◽  
Shuyun Feng ◽  
Tingli Zhao ◽  
Zhengzheng Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Cyclin D ◽  
Dna Relaxation ◽  
Cycle Arrest ◽  
H460 Cell ◽  
H1975 Cell

Objective: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. Background: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. Methods: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. Results: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. Conclusion: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.

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