Search results for "DNA DAMAGE"
showing 10 items of 534 documents
Chromatin modifiers and recombination factors promote a telomere fold-back structure, that is lost during replicative senescence.
2020
Telomeres have the ability to adopt a lariat conformation and hence, engage in long and short distance intra-chromosome interactions. Budding yeast telomeres were proposed to fold back into subtelomeric regions, but a robust assay to quantitatively characterize this structure has been lacking. Therefore, it is not well understood how the interactions between telomeres and non-telomeric regions are established and regulated. We employ a telomere chromosome conformation capture (Telo-3C) approach to directly analyze telomere folding and its maintenance in S. cerevisiae. We identify the histone modifiers Sir2, Sin3 and Set2 as critical regulators for telomere folding, which suggests that a dis…
Oxidative DNA damage and disturbance of antioxidant capacity by alternariol in Caco-2 cells
2015
Oxidative stress occurs as a consequence of an imbalance between the prooxidant/antioxidant systems, causing an increase of intracellular generation of reactive oxygen species. Alternariol (AOH), a mycotoxin produced by Alternaria sp. can alter the action of glutathione (GSH) and the enzymes involved in the redox system, causing damage to cellular macromolecules such as DNA. The aims of this work were to determine the induction of oxidative stress by the antioxidant defenses imbalance in relation to glutathione (GSH), glutathione reductase (GR), glutathione transferase (GST), glutathione peroxidase (GPx) levels and DNA damage in Caco-2 cells derived from adenocarcinoma human colon. Oxidativ…
Destabilized green fluorescent protein detects rapid removal of transcription blocks after genotoxic exposure
2007
High stabilities of reporter proteins and their messenger RNAs (mRNAs) interfere with the detection of rapid transient changes in gene expression, such as transcriptional blocks posed by genotoxic DNA lesions. We have modified a green fluorescent protein (GFP) gene within the episomal pMARS vector by addition of a fragment encoding for mouse ornithine decarboxylase (ODC) proline-glutamate-serine-threonine-rich (PEST) sequence in order to target the protein to the proteasomes and achieved an unprecedentedly fast GFP turnover in permanently transfected human cells. As early as 1 h after inhibition of protein synthesis by cycloheximide, the number of fluorescent cells decreased more than 5-fo…
Transcription, apoptosis and p53: catch-22
2005
The tumor suppressor p53 is a transcription factor and is activated in response to DNA damage or oncogenic transformation through modification of its interaction with regulatory proteins. The transcription factor activity of p53 is thought to mediate its primary functions of cell-cycle arrest and apoptosis through the gene expression it regulates, and evidence to support this interpretation continues to accumulate. However, reports of transcription-independent activities of p53, especially in the induction of apoptosis, persist. In particular, recent studies suggest that cytosolic p53 directly interacts with members of the BCL-2 family of apoptosis regulators, thereby triggering mitochondri…
The repair of oxidized purines in the DNA of human lymphocytes requires an activation involving NF-YA-mediated upregulation of OGG1.
2014
8-Oxoguanine DNA glycosylase (OGG1), which initiates the repair of DNA purine modifications such as 8-oxo-7,8-dihydroguanine (8-oxoG), is often regarded as a house keeping protein ubiquitously active in mammalian cells. We have analysed the repair rates of oxidized purines generated by photosensitization in peripheral human lymphocytes and observed that the cells were virtually unable to remove these lesions (less than 10% removal within 24h). However, stimulation of the lymphocytes with phytohemagglutinin (PHA) strongly accelerated the repair so that ∼30% of the lesions were repaired within 4h. Within 24h following PHA stimulation and preceding the induction of cell proliferation, Western …
Protease-mediated processing of Argonaute proteins controls small RNA association
2020
SummarySmall RNA pathways defend the germlines of animals against selfish genetic elements and help to maintain genomic integrity. At the same time, their activity needs to be well-controlled to prevent silencing of ‘self’ genes. Here, we reveal a proteolytic mechanism that controls endogenous small interfering (22G) RNA activity in the Caenorhabditis elegans germline to protect genome integrity and maintain fertility. We find that WAGO-1 and WAGO-3 Argonaute (Ago) proteins are matured through proteolytic processing of their unusually proline-rich N-termini. In the absence of DPF-3, a P-granule-localized N-terminal dipeptidase orthologous to mammalian DPP8/9, processing fails, causing a cha…
Pyrrolo[2,3-h]quinolinones: A new ring system with potent photoantiproliferative activity
2006
A new class of compounds, the pyrrolo[2,3-h]quinolin-2-ones, nitrogen isosters of the angular furocoumarin Angelicin, was synthesized with the aim of obtaining new photochemotherapeutic agents with increased antiproliferative activity and lower undesired toxic effects than the lead compound. Two synthetic pathways were approached to allow the isolation both of the dihydroderivatives 10-17 and of the aromatic ring system 23. Compounds 10-17 showed a remarkable phototoxicity and a great UVA dose dependence reaching IC(50) values at submicromolar level. Intracellular localization of these compounds has been evaluated by means of fluorescence microscopy using tetramethylrhodamine methyl ester a…
Challenging Dogma: Thresholds for Genotoxic Carcinogens? The Case of Vinyl Acetate
2002
Although many questions remain unanswered, the general principle of the sequence of events leading to cancer after exposure to genotoxic carcinogens has become increasingly clear. This helps to understand the parameters that influence the shape of the dose-effect curve for carcinogenesis, including metabolic activation and inactivation of carcinogens, DNA repair, cell cycle control, apoptosis, and control by the immune system. A linear dose-response relationship with no observable threshold seems to be a conservative but adequate description for the carcinogenic activity of many genotoxic carcinogens, such as aflatoxin B1, the tobacco-specific nitrosoketone NNK, and probably N,N-diethylnit…
alpha-Tocopherol, MDA-HNE and 8-OHdG levels in liver and heart mitochondria of adriamycin-treated rats fed with alcohol-free beer.
2008
Different studies indicate that oxidative stress and mitochondrial damage are key factors in different pathogenic process. The aim of this study was to investigate the possible protective role of alcohol-free beer on adriamycin-induced (ADR) heart and liver toxicity using biomarkers of oxidative stress. This effect was compared with the effect of alcohol beer intake and with a control group. Rats were randomly divided into six groups. The first group received no adriamycin, was fed with water and was regarded as the control group; the second group was injected with a ADR (two cycles of 5mg/kg); the third and fourth groups were fed with alcohol-free and beer for 21 days, respectively and the…
Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy
2016
AbstractInactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anti-cancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criter…