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At least 217 records · Page 12Linked to original sources
PubMed2001

DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326.

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. Transcriptional analyses of OGG1 showed the expression of two isoforms, 1a and b, in lymphocytes. Structural analysis of the human OGG1 (hOGG1) gene revealed a Ser326/Cys326 polymorphism in the Caucasian population with allele frequencies of 75% for Ser326 and 25% for Cys326. This polymorphism was not associated with altered OGG1 activity. The described routine test system for measuring OGG1 activity in cryopreserved lymphocytes provided highly reproducible results and is a useful tool for risk assessment associated with alterations in the repair of oxidative DNA damage.

Alleles↗
PubMed1999

A phylogenomic study of DNA repair genes, proteins, and processes.

The ability to recognize and repair abnormal DNA structures is common to all forms of life. Studies in a variety of species have identified an incredible diversity of DNA repair pathways. Documenting and characterizing the similarities and differences in repair between species has important value for understanding the origin and evolution of repair pathways as well as for improving our understanding of phenotypes affected by repair (e.g., mutation rates, lifespan, tumorigenesis, survival in extreme environments). Unfortunately, while repair processes have been studied in quite a few species, the ecological and evolutionary diversity of such studies has been limited. Complete genome sequences can provide potential sources of new information about repair in different species. In this paper, we present a global comparative analysis of DNA repair proteins and processes based upon the analysis of available complete genome sequences. We use a new form of analysis that combines genome sequence information and phylogenetic studies into a composite analysis we refer to as phylogenomics. We use this phylogenomic analysis to study the evolution of repair proteins and processes and to predict the repair phenotypes of those species for which we now know the complete genome sequence.

Adenosine Triphosphatases↗
PubMed2001

The pso mutants of Saccharomyces cerevisiae comprise two groups: one deficient in DNA repair and another with altered mutagen metabolism.

Yeast mutants that are sensitive to photoactivated psoralens, named pso mutants, were isolated and described more than 20 years ago. Nine genes responsible for the pso phenotypes were identified and seven of them cloned and molecularly characterized. Of the nine PSO genes of yeast seven apparently encode proteins involved in the repair of DNA lesions generated by photoinduced psoralens and by other mutagens, while two, PSO6 and PSO7, are responsible for structural elements of the membrane and for a functional respiratory chain, respectively. Of the seven proven or putative DNA repair genes six directly or indirectly control induced mutagenesis. Four of these PSO loci were found allelic to already known repair genes, whereas two, PSO2 and PSO4, represent new genes involved in DNA repair and in repair/pre-mRNA processing in S. cerevisiae. Gene PSO2 encodes a protein indispensable for repair of DNA interstrand cross-links that are produced by a variety of bi- and poly-functional mutagens and that appears to be important for a likewise repair function in humans as well.

DNA Repair↗
PubMedDate not supplied

Normal human keratinocytes pretreated with damaged mRNA are resistant to UVB damage and exhibit increased DNA repair.

Treatment of normal human keratinocytes with UVC-irradiated rabbit globin mRNA 24 h before and after UVB exposure increased the survival of the human keratinocytes. We also observed that UVC-damaged mRNA reduced the formation of sunburn cells in skin models. We next tested the effects of UVC-damaged mRNA on cellular repair of DNA. DNA repair was evaluated using 2 assay methods. The first method used a damaged plasmid that is transfected back into the cell where it is repaired by the host cell repair mechanism. In these experiments, we observed that externally added UVC-damaged rabbit globin mRNA enhanced the repair of a plasmid transfected into the host keratinocyte cells. The second method used to determine the effects on DNA repair was direct immunostaining for thymidine-thymidine dimers (TT dimers) in histological sections of the skin models. Skin models were irradiated with UVB and then fixed immediately or after 24 h and stained for TT dimers. UVB irradiation immediately caused an increase in the number of stained keratinocytes in the skin. The number of stained cells decreased in skin fixed 24 h after UVB. This is due to repair of the TT dimers and their removal. Sections of skin models pretreated with UV-damaged mRNA exhibit greater removal of these TT dimers after 24 h. The above evidence suggests that damaged mRNA can trigger a host cell DNA repair pathway.

Animals↗
PubMed2002

Focus-formation of replication protein A, activation of checkpoint system and DNA repair synthesis induced by DNA double-strand breaks in Xenopus egg extract.

The response to DNA damage was analyzed using a cell-free system consisting of Xenopus egg extract and demembranated sperm nuclei. In the absence of DNA-damaging agents, detergent-resistant accumulation of replication protein A appeared in nuclei after a 30 minute incubation, and a considerable portion of the replication protein A signals disappeared during a further 30 minute incubation. Similar replication protein A accumulation was observed in the nuclei after a 30 minute incubation in the extract containing camptothecin, whereas a further 30 minute incubation generated discrete replication protein A foci. The addition of camptothecin also induced formation of gamma-H2AX foci, which have been previously shown to localize at sites of DSBs. Analysis of the time course of DNA replication and results obtained using geminin, an inhibitor of licensing for DNA replication, suggest that the discrete replication protein A foci formed in response to camptothecin-induced DNA damage occur in a DNA-replication-dependent manner. When the nuclei were incubated in the extract containing EcoRI, discrete replication protein A foci were observed at 30 minutes as well as at 60 and 90 minutes after incubation, and the focus-formation of replication protein A was not sensitive to geminin. DNA replication was almost completely inhibited in the presence of EcoRI and the inhibition was sensitive to caffeine, an inhibitor of ataxia telangiectasia mutated protein (ATM) and ATM- and Rad3-related protein (ATR). However, the focus-formation of replication protein A in the presence of EcoRI was not influenced by caffeine treatment. EcoRI-induced incorporation of biotin-dUTP into chromatin was observed following geminin-mediated inhibition of DNA replication, suggesting that the incorporation was the result of DNA repair. The biotin-dUTP signal co-localized with replication protein A foci and was not significantly suppressed or stimulated by the addition of caffeine.

Animals↗
PubMed1994

Mutational analysis of ERCC3, which is involved in DNA repair and transcription initiation: identification of domains essential for the DNA repair function.

The human ERCC3 gene, which corrects specifically the nucleotide excision repair defect in human xeroderma pigmentosum group B and cross-complements the repair deficiency in rodent UV-sensitive mutants of group 3, encodes a presumed DNA helicase that is identical to the p89 subunit of the general transcription factor TFIIH/BTF2. To examine the significance of the postulated functional domains in ERCC3, we have introduced mutations in the ERCC3 cDNA by means of site-specific mutagenesis and have determined the repair capacity of each mutant to complement the UV-sensitive phenotype of rodent group 3 cells. A conservative substitution of arginine for the invariant lysine residue in the ATPase motif (helicase domain I), six deletion mutations in the other helicase domains, and a deletion in the potential helix-turn-helix DNA-binding motif fail to complement the ERCC3 excision repair defect of rodent group 3 mutants, which implies that the helicase domains as well as the potential DNA-binding motif are required for the repair function of ERCC3. Analysis of carboxy-terminal deletions suggests that the carboxy-terminal exon may comprise a distinct determinant for the DNA repair function. In addition, we show that a functional epitope-tagged version of ERCC3 accumulates in the nucleus. Deletion of the putative nuclear location signal impairs neither the nuclear location nor the repair function, indicating that other sequences may (also) be involved in translocation of ERCC3 to the nucleus.

Amino Acid Sequence↗
PubMed1992

DNA repair.

Explore the source record for details and available documents.

DNA Repair↗
PubMed1990

Kinetics and mechanism of DNA repair. Evaluation of caged compounds for use in studies of u.v.-induced DNA repair.

Experiments are described in which the feasibility of using caged dideoxy and other nucleoside triphosphate analogues for trapping breaks induced by u.v. radiation damage to mammalian cell DNA is evaluated. These nucleotide analogues that have a photolabile 1-(2-nitrophenyl)ethyl-protecting group attached to the gamma-phosphate are placed in situ by permeabilizing cells by exposure to hypo-osmotic medium. The nucleoside triphosphate is released from the cage by a 351 nm u.v. laser pulse whence it may incorporate in the growing chain of DNA induced by the excision-repair process and terminate chain elongation. If the photoreleased dideoxynucleoside triphosphate is isotopically labelled in the alpha-phosphate position the break is trapped and labelled. Incorporation of radioactivity into trichloroacetic acid insoluble material in these experiments confirms their potential for use in studies of the kinetics of mammalian cell DNA repair.

Animals↗
PubMed1988

[Mechanisms of DNA repair disorders in human cells. Genome instability in lymphocytes of patients with myopathy related to DNA repair disorders].

Increased level of cytogenetic damages was observed in lymphocytes of 10 patients with muscular dystrophy (Duchenne, Erba, Landuzi--Degerin). Analysis of DNA repair synthesis revealed inhibition of this process in lymphocytes of 10 patients observed. On the other hand, decreased reactivation of vaccinia virus and increased level of virus mutagenesis induced by 4-nitroquinoline-1-oxide and bleomycin was noted in the experiments with lymphocytes of 3 patients observed.

4-Nitroquinoline-1-oxide↗
PubMed1979

Induction of the DNA repair enzyme uracil-DNA glycosylase in stimulated human lymphocytes.

The capacity of human cells to modulate the synthesis of DNA repair enzymes has been investigated by measuring the induction of the uracil-DNA glycosylase during lymphocyte stimulation. Treatment of peripheral lymphocytes with phytohemagglutinin increased glycosylase activity 10-fold. Glycosylase stimulation was coordinate with the activation of DNA synthesis and DNA polymerase activity. Two chromatographically distinct species of the glycosylase have been resolved; only one species is induced during phytohemagglutinin stimulation. The effect of actinomycin D and cycloheximide on glycosylase induction was determined. Treatment with either inhibitor at 96 hr after phytohemagglutinin addition (maximal induction) decreased glycosylase activity after an appreciable lag period. This suggested that induction of the uracil-DNA glycosylase requires transcription and translation although the enzyme may be quite stable once induced.

Cycloheximide↗
PubMedDate not supplied

The mechanism of DNA repair by uracil-DNA glycosylase: studies using nucleotide analogues.

2',4'-Dideoxy-4'-methyleneuridine incorporated into oligodeoxynucleotides forms regular B-DNA duplexes as shown by Tm and CD measurements. Such oligomers are not cleaved by the DNA repair enzyme, UDG, which cleaves the glycosylic bond in dU but not in dT nor in dC nucleosides in single stranded and double stranded DNA. Differential binding of oligomers containing carbadU, 4'-thiodU, and dU residues to wild type and mutant UDG proteins identify an essential role for the furanose 4'-oxygen in recognition and cleavage of dU residues in DNA.

Base Sequence↗
PubMed2000

A deficiency in DNA repair and DNA-PKcs expression in the radiosensitive BALB/c mouse.

We have studied the efficiency of DNA double strand break (DSB) rejoining in primary cells from mouse strains that show large differences in in vivo radiosensitivity and tumor susceptibility. Cells from radiosensitive, cancer-prone BALB/c mice showed inefficient end joining of gamma ray-induced DSBs as compared with cells from all of the other commonly used strains and F1 hybrids of C57BL/6 and BALB/c mice. The BALB/c repair phenotype was accompanied by a significantly reduced expression level of DNA-PKcs protein as well as a lowered DNA-PK activity level as compared with the other strains. In conjunction with published reports, these data suggest that natural genetic variation in nonhomologous end joining processes may have a significant impact on the in vivo radiation response of mice.

Animals↗
PubMed2006

Association between polymorphisms of DNA repair gene XRCC1 and DNA damage in asbestos-exposed workers.

OBJECTIVE: To compare the asbestos-induced DNA damage and repair capacities of DNA damage between 104 asbestos-exposed workers and 101 control workers in Qingdao City of China and to investigate the possible association between polymorphisms in codon 399 of XRCC1 and susceptibility to asbestosis. METHODS: DNA damage levels in peripheral blood lymphocytes were determined by comet assay, and XRCC1 genetic polymorphisms of DNA samples from 51 asbestosis cases and 53 non-asbestosis workers with a similar asbestos exposure history were analyzed by PCR/RFLP. RESULTS: The basal comet scores (3.95 +/- 2.95) were significantly higher in asbestos-exposed workers than in control workers (0.10 +/- 0.28). After 1 h H2O2 stimulation, DNA damage of lymphocytes exhibited different increases. After a 4 h repair period, the comet scores were 50.98 +/- 19.53 in asbestos-exposed workers and 18.32 +/- 12.04 in controls. The residual DNA damage (RD) was significantly greater (P<0.01) in asbestos-exposed workers (35.62%) than in controls (27.75%). XRCC1 genetic polymorphism in 104 asbestos-exposed workers was not associated with increased risk of asbestosis. But compared with polymorphisms in the DNA repair gene XRCC1 (polymorphisms in codon 399) and the DNA damage induced by asbestos, the comet scores in asbestosis cases with Gln/Gln, Gln/Arg, and Arg/Arg were 40.26 +/- 18.94, 38.03 +/- 28.22, and 32.01 +/- 11.65, respectively, which were higher than those in non-asbestosis workers with the same genotypes (25.58 +/- 11.08, 37.08 +/- 14.74, and 29.38 +/- 10.15). There were significant differences in the comet scores between asbestosis cases and non-asbestosis workers with Gln/Gln by Student's t-test (P<0.05 or 0.01). The comet scores were higher in asbestosis workers with Gln/Gln than in those with Arg/Arg and in non-asbestosis workers exposed to asbestos, but without statistically significant difference. CONCLUSIONS: Exposure to asbestos may be related to DNA damage or the capacity of cells to repair H2O2-induced DNA damage. DNA repair gene XRCC1 codon 399 may be responsible for the inter-individual susceptibility in DNA damage and repair capacities.

Adult↗
PubMed2002

DNA repair during organogenesis.

DNA damage caused by genotoxic agents can impact on virtually any cellular process due to its ability to affect gene expression and subsequent gene products. The importance of repairing damaged DNA is evidenced by the variety of DNA repair pathways that have evolved in all living organisms, and the human syndromes caused by a lack of this repair ability. This review focuses on the expression and activity of DNA repair pathways during mammalian organogenesis, and the role of these pathways in ensuring the stability of the conceptal genome. DNA repair capacity may play a role also in the response of the conceptus to genotoxic agents that may induce malformations; the consequences of exposure to a genotoxic agent during organogenesis depend on the extent of the damage and on the ability of the embryo to respond by repairing DNA or arresting cell division. The four main repair pathways (nucleotide excision repair, base excision repair, mismatch repair, and recombination repair) are expressed to various degrees during organogenesis, as are members of the genotoxic stress-activated cell cycle checkpoint pathways. Developmental-stage-specific alterations in transcript levels, protein levels, as well as activity, indicate that the regulation of DNA repair pathways during development is complex. The importance of DNA repair pathways in endogenous damage control is illustrated by the sensitivity of development to their disruption if some of these genes are mutated. Furthermore, the conceptus has a limited capacity to alter DNA repair responses following exposure to genotoxic agents.

Animals↗
PubMed1992

Intracellular localization of human DNA repair enzyme methylguanine-DNA methyltransferase by antibodies and its importance.

The human DNA repair enzyme, methylguanine-DNA methyltransferase (MGMT, M(r) 21,000), which protects cells against the mutagenic effect of alkylating carcinogens, was found to be localized in the cell nucleus (except the nucleolus) by immunofluorescence staining using polyclonal and monoclonal antibodies. The supporting experiments came from differential staining of the MGMT-deficient (mer-) and -proficient (mer+) cells, Western blotting analysis, and specific antibody depletion studies with the immobilized fusion protein, GSTMGMT-glutathione-Sepharose. Its localization in the nucleus agrees with its biological function and possibly explains the ineffective protection of mammalian cells (mer-) transfected with the Escherichia coli MGMT genes from bifunctional alkylating agents.

Amino Acid Sequence↗