A Novel Approach to DNA Damage Assessments: Measurement of the Thymine Glycol Lesion

2006 ◽  
Vol 165 (4) ◽  
pp. 438-444 ◽  
Author(s):  
Douglas T. Bailey ◽  
Han-Chun C. DeFedericis ◽  
Kellee F. Greene ◽  
Herbert Iijima ◽  
Edwin E. Budzinski ◽  
...  
Keyword(s):  
Dna Damage ◽  
Thymine Glycol ◽  
Novel Approach

Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3796-3800 ◽  
Author(s):  
Ronan T. Swords ◽  
Kevin R. Kelly ◽  
Peter G. Smith ◽  
James J. Garnsey ◽  
Devalingam Mahalingam ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Stress Responses ◽  
Myeloid Leukemia ◽  
Cell Cycle Progression ◽  
Reactive Oxygen Species Generation ◽  
Nuclear Factor Κb ◽  
Redox Status ◽  
Novel Approach ◽  
Acute Myeloid

Abstract NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-κB activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDylated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML.

scholarly journals Novel insights into the mode of action of 1,4-dioxane using a systems screening approach

2020 ◽  
Author(s):  
Georgia Charkoftaki ◽  
Jaya Prakash Golla ◽  
Alvaro Santos-Neto ◽  
David J. Orlicky ◽  
Rolando Garcia-Milian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Drinking Water ◽  
Immunohistochemical Analysis ◽  
The United States ◽  
Environmental Chemicals ◽  
Dna Double Strand Breaks ◽  
Dna Damage And Repair ◽  
Mechanisms Of Toxicity ◽  
Novel Approach ◽  
Histopathological Studies

Abstract1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

scholarly journals Impact of Replication Stress in Human Papillomavirus Pathogenesis

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Cary A. Moody
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Human Papillomavirus ◽  
Genomic Instability ◽  
Viral Persistence ◽  
Replication Stress ◽  
Cell Cycle Checkpoints ◽  
Premalignant Lesions ◽  
Associated Lesions ◽  
Novel Approach

ABSTRACTThe inactivation of critical cell cycle checkpoints by the human papillomavirus (HPV) oncoprotein E7 results in replication stress (RS) that leads to genomic instability in premalignant lesions. Intriguingly, RS tolerance is achieved through several mechanisms, enabling HPV to exploit the cellular RS response for viral replication and to facilitate viral persistence in the presence of DNA damage. As such, inhibitors of the RS response pathway may provide a novel approach to target HPV-associated lesions and cancers.

Identification of dose-dependent DNA damage and repair responses from subchronic exposure to 1,4-dioxane in mice using a systems analysis approach

2021 ◽  
Author(s):  
Georgia Charkoftaki ◽  
Jaya Prakash Golla ◽  
Alvaro Santos-Neto ◽  
David J Orlicky ◽  
Rolando Garcia-Milian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Drinking Water ◽  
Immunohistochemical Analysis ◽  
The United States ◽  
Environmental Chemicals ◽  
Dna Double Strand Breaks ◽  
Dna Damage And Repair ◽  
Mechanisms Of Toxicity ◽  
Novel Approach ◽  
Histopathological Studies

Abstract 1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

scholarly journals Estimation of oxidative DNA damage in man from urinary excretion of repair products.

1998 ◽  
Vol 45 (1) ◽  
pp. 133-144 ◽  
Author(s):  
S Loft ◽  
H E Poulsen
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Nuclear Dna ◽  
Inflammatory Diseases ◽  
Average Rate ◽  
Energy Restriction ◽  
Dna Lesions ◽  
Water Soluble ◽  
Nucleotide Synthesis ◽  
Thymine Glycol

DNA is constantly damaged and repaired in living cells. The repair products of the oxidative DNA lesions, i.e. oxidised nucleosides and bases, are poor substrates for the enzymes involved in nucleotide synthesis, are fairly water soluble, and generally excreted into the urine without further metabolism. Among the possible products, 8-oxo-2'-deoxyguanosine, 8-oxoguanine, thymine glycol, thymidine glycol and, 5-hydroxymethyluracil have so far been identified in urine. It should be emphasised that the excretion of the repair products in urine represents the average rate of damage in the total body whereas the level of oxidised bases in nuclear DNA is a concentration measurement in that specific tissue/cells in the moment of sampling. The rate of oxidative DNA modifications has been studied in humans by means of the repair products as urinary biomarkers, particularly with respect to 8-oxo-2'-deoxyguanosine. The data obtained so far indicate that the important determinants of the oxidative damage rate include tobacco smoking, oxygen consumption and some inflammatory diseases whereas diet composition, energy restriction and antioxidant supplements have but a minimal influence, possibly with the exception of yet unidentified phytochemicals, e.g. from cruciferous vegetables. The data are consistent with the experimentally based notion that oxidative DNA damage is an important mutagenic and apparently carcinogenic factor. However, the proof of a causal relationship in humans is still warranted. In the future the use of biomarkers may provide this evidence and allow further investigations on the qualitative and quantitative importance of oxidative DNA modification and carcinogenesis in man, as well as elucidate possible preventive measures.

scholarly journals γ-H2AX Foci Persistence at Chromosome Break Suggests Slow and Faithful Repair Phases Restoring Chromosome Integrity

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1397 ◽  
Author(s):  
Michelle Ricoul ◽  
Tamizh Selvan Gnana Sekaran ◽  
Patricia Brochard ◽  
Cecile Herate ◽  
Laure Sabatier
Keyword(s):  
Dna Damage ◽  
Chromosome Rearrangement ◽  
Chromosome Break ◽  
Dna Double Strand Breaks ◽  
Chromosome Fusion ◽  
Post Irradiation ◽  
Dna Lesion ◽  
Novel Approach ◽  
Chromosome Integrity ◽  
Kinetics Of

Many toxic agents can cause DNA double strand breaks (DSBs), which are in most cases quickly repaired by the cellular machinery. Using ionising radiation, we explored the kinetics of DNA lesion signaling and structural chromosome aberration formation at the intra- and inter-chromosomal level. Using a novel approach, the classic Premature Chromosome Condensation (PCC) was combined with γ-H2AX immunofluorescence staining in order to unravel the kinetics of DNA damage signalisation and chromosome repair. We identified an early mechanism of DNA DSB joining that occurs within the first three hours post-irradiation, when dicentric chromosomes and chromosome exchanges are formed. The slower and significant decrease of ”deleted chromosomes” and 1 acentric telomere fragments observed until 24 h post-irradiation, leads to the conclusion that a second and error-free repair mechanism occurs. In parallel, we revealed remaining signalling of γ-H2AX foci at the site of chromosome fusion long after the chromosome rearrangement formation. Moreover there is important signalling of foci on the site of telomere and sub-telomere sequences suggesting either a different function of γ-H2AX signalling in these regions or an extreme sensibility of the telomere sequences to DNA damage that remains unrepaired 24 h post-irradiation. In conclusion, chromosome repair happens in two steps, including a last and hardly detectable one because of restoration of the chromosome integrity.

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