Search results for "Glycosylase"
showing 10 items of 53 documents
Study of the Mode and Efficiency of DNA Binding in the Damage Induced by Photoactivated Water Soluble Porphyrins
2013
We have investigated the DNA binding interactions and in vitro photoactivated DNA damage induced by a neutral water soluble porphyrin derivative 5,10,15,20-tetrakis(2,4,6-trihydroxyphenyl)porphyrin (TTHPP) and its zinc derivative 5,10,15,20-tetrakis(2,4,6-trihydroxyphenyl)porphyrinato zinc(II) (Zn-TTHPP) upon visible light irradiation through various spectroscopic techniques and employing repair endonucleases. These porphyrin derivatives exhibited high affinity toward DNA through groove binding interactions as evidenced through the UV-vis absorption, emission, circular dichroism spectral and viscosity changes. Interestingly, the free base porphyrin derivative, TTHPP generated efficient sing…
Rapid inactivation and proteasome-mediated degradation of OGG1 contribute to the synergistic effect of hyperthermia on genotoxic treatments
2013
Inhibition of DNA repair has been proposed as a mechanism underlying heat-induced sensitization of tumour cells to some anticancer treatments. Base excision repair (BER) constitutes the main pathway for the repair of DNA lesions induced by oxidizing or alkylating agents. Here, we report that mild hyperthermia, without toxic consequences per se, affects cellular DNA glycosylase activities, thus impairing BER. Exposure of cells to mild hyperthermia leads to a rapid and selective inactivation of OGG1 (8-oxoguanine DNA glycosylase) associated with the relocalisation of the protein into a detergent-resistant cellular fraction. Following its inactivation, OGG1 is ubiquitinated and directed to pro…
The elemental role of iron in DNA synthesis and repair
2017
Iron is an essential redox element that functions as a cofactor in many metabolic pathways. Critical enzymes in DNA metabolism, including multiple DNA repair enzymes (helicases, nucleases, glycosylases, demethylases) and ribonucleotide reductase, use iron as an indispensable cofactor to function. Recent striking results have revealed that the catalytic subunit of DNA polymerases also contains conserved cysteine-rich motifs that bind iron–sulfur (Fe/S) clusters that are essential for the formation of stable and active complexes. In line with this, mitochondrial and cytoplasmic defects in Fe/S cluster biogenesis and insertion into the nuclear iron-requiring enzymes involved in DNA synthesis a…
The Friedreich's Ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals
2010
DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frata…
Oxidative DNA damage induced by visible light in mammalian cells: extent, inhibition by antioxidants and genotoxic effects
1998
The extent of the indirect DNA damage generated in mammalian cells by visible light because of the presence of endogenous photosensitizers was studied by means of repair endonucleases. In immortalized human keratinocytes (HaCaT cells) exposed to low doses of natural sunlight, the yield of oxidative DNA base modifications sensitive to the repair endonuclease formamidopyrimidine-DNA glycosylase (Fpg protein) generated by this indirect mechanism was 10% of that of pyrimidine dimers (generated by direct DNA excitation). A similar yield of Fpg-sensitive modifications, which include 8-hydroxyguanine, was observed in primary keratinocytes. The relative yield of oxidative base modifications decreas…
Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility
2013
In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a followup of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimate…
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients
2018
Rationale: Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. Objective: To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs. Methods and Results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis reveale…
Constitutive expression and inducibility of O6-methylguanine-DNA methyltransferase and N-methylpurine-DNA glycosylase in rat liver cells exhibiting d…
1995
AbstractWe have analyzed the expression of the DNA repair genes O6-methylguanine-DNA methyltransferase (MGMT) and N-methylpurine-DNA glycosylase (MPG) at RNA and protein activity level in primary rat hepatocytes in vitro and various rat hepatoma cell lines exhibiting different status of differentiation. The basal level of MGMT mRNA and activity correlated well with the degree of differentiation, as measured by tyrosine aminotransferase (TAT) mRNA expression. Induction of MGMT mRNA and protein activity by X-ray and Nmethyl-N′-nitro-N-nitrosoguanidine (MNNG) treatment was most pronounced in the well-differentiated hepatocytes and in various differentiated hepatoma cell lines (up to 6-fold). T…
DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326.
2001
8-oxoguanine DNA glycosylase 1 (OGG1) is a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine (8oxoG) from DNA. Since 8oxoG is a highly mispairing lesion, decreased OGG1 expression level could lead to a higher background mutation frequency and could possibly increase the cancer risk of an individual under oxidative stress. In order to analyse the natural variation of OGG1, we measured the DNA repair activity in human lymphocytes of healthy individuals by means of an 8oxoG-containing oligonucleotide assay. The data obtained revealed a two fold interindividual variation of OGG1 activity in lymphocytes. There was no difference in OGG1 activity due to gender and smoking behaviour. Transcri…
The basal levels of 8-oxoG and other oxidative modifications in intact mitochondrial DNA are low even in repair-deficient (Ogg1(-/-)/Csb(-/-)) mice.
2007
Abstract Mitochondrial DNA (mtDNA) is assumed to be highly prone to damage by reactive oxygen species (ROS) because of its location in close proximity to the mitochondrial electron transport chain. Accordingly, mitochondrial oxidative DNA damage has been hypothesized to be responsible for various neurological diseases, ageing and cancer. Since 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most frequent oxidative base modifications, is removed from the mitochondrial genome by the glycosylase OGG1, the basal levels of this lesion are expected to be highly elevated in Ogg1−/− mice. To investigate this hypothesis, we have used a mtDNA relaxation assay in combination with various repair enzymes …