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At least 307 records · Page 17Linked to original sources
PubMed1999

Changes in expression of the DNA repair protein complex DNA-dependent protein kinase after ischemia and reperfusion.

Reperfusion of ischemic tissue causes an immediate increase in DNA damage, including base lesions and strand breaks. Damage is reversible in surviving regions indicating that repair mechanisms are operable. DNA strand breaks are repaired by nonhomologous end joining in mammalian cells. This process requires DNA-dependent protein kinase (DNA-PK), composed of heterodimeric Ku antigen and a 460,000 Da catalytic subunit (DNA-PKcs). In this study, a rabbit spinal cord model of reversible ischemia was used to demonstrate the effect of acute CNS injury on the activity and expression of DNA-dependent protein kinase. The DNA-binding activity of Ku antigen, analyzed by an electrophoretic mobility shift assay, increased during reperfusion after a short ischemic insult (15 min of occlusion), from which the animals recover neurological function. After severe ischemic injury (60 min of occlusion) and reperfusion that results in permanent paraplegia, Ku DNA binding was reduced. Protein levels of the DNA-PK components-Ku70, Ku80, and DNA-PKcs-were monitored by immunoblotting. After 60 min of occlusion, the amount of DNA-PKcs and the enzyme poly(ADP-ribose) polymerase (PARP) decreased with the same time course during reperfusion. Concurrently 150 and 120 kDa fragments were immunostained by an anti-DNA-PKcs monoclonal antibody. This antibody was shown to cross-react with alpha-fodrin breakdown products. The 120 kDa fodrin peptide is associated with caspase-3 activation during apoptosis. Both DNA-PKcs and PARP are also substrates for caspase-3-like activities. The results are consistent with a model in which after a short ischemic insult, DNA repair proteins such as DNA-PK are activated. After severe ischemic injury, DNA damage overwhelms repair capabilities, and cell death programs are initiated.

Animals↗
PubMed1998

A broadening view of recombinational DNA repair in bacteria.

Recombinational DNA repair is both the most complex and least understood of DNA repair pathways. In bacterial cells grown under normal laboratory conditions (without a DNA damaging treatment other than an aerobic environment), a substantial number (10-50%) of the replication forks originating at oriC encounter a DNA lesion or strand break. When this occurs, repair is mediated by an elaborate set of recombinational DNA repair pathways which encompass most of the enzymes involved in DNA metabolism. Four steps are discussed: (i) The replication fork stalls and/or collapses. (ii) Recombination enzymes are recruited to the location of the lesion, and function with nearly perfect efficiency and fidelity. (iii) Additional enzymatic systems, including the phiX174-type primosome (or repair primosome), then function in the origin-independent reassembly of the replication fork. (iv) Frequent recombination associated with recombinational DNA repair leads to the formation of dimeric chromosomes, which are monomerized by the XerCD site-specific recombination system.

Bacteria↗
PubMed2002

Further phenotypic characterization of pso mutants of Saccharomyces cerevisiae with respect to DNA repair and response to oxidative stress.

The sensitivity responses of seven pso mutants of Saccharomyces cerevisiae towards the mutagens N-nitrosodiethylamine (NDEA), 1,2:7,8-diepoxyoctane (DEO), and 8-hydroxyquinoline (8HQ) further substantiated their allocation into two distinct groups: genes PSO1 (allelic to REV3), PSO2 (SNM1), PSO4 (PRP19), and PSO5 (RAD16) constitute one group in that they are involved in repair of damaged DNA or in RNA processing whereas genes PSO6 (ERG3) and PSO7 (COX11) are related to metabolic steps protecting from oxidative stress and thus form a second group, not responsible for DNA repair. PSO3 has not yet been molecularly characterized but its pleiotropic phenotype would allow its integration into either group. The first three PSO genes of the DNA repair group and PSO3, apart from being sensitive to photo-activated psoralens, have another common phenotype: they are also involved in error-prone DNA repair. While all mutants of the DNA repair group and pso3 were sensitive to DEO and NDEA the pso6 mutant revealed WT or near WT resistance to these mutagens. As expected, the repair-proficient pso7-1 and cox11-Delta mutant alleles conferred high sensitivity to NDEA, a chemical known to be metabolized via redox cycling that yields hydroxylamine radicals and reactive oxygen species. All pso mutants exhibited some sensitivity to 8HQ and again pso7-1 and cox11-Delta conferred the highest sensitivity to this drug. Double mutant snm1-Delta cox11-Delta exhibited additivity of 8HQ and NDEA sensitivities of the single mutants, indicating that two different repair/recovery systems are involved in survival. DEO sensitivity of the double mutant was equal or less than that of the single snm1-Delta mutant. In order to determine if there was oxidative damage to nucleotide bases by these drugs we employed an established bacterial test with and without metabolic activation. After S9-mix biotransformation, NDEA and to a lesser extent 8HQ, lead to significantly higher mutagenesis in an Escherichia coli tester strain WP2-IC203 as compared to WP2, whereas DEO-induced mutagenicity remained unchanged.

DNA Damage↗
PubMed1980

Mechanism of the ATP effect in the DNA repair synthesis of gamma-irradiated Escherichia coli cells.

Gamma-irradiation of Escherichia coli cells made permeable to deoxynucleoside triphosphates (dNTP) by toluene induces a repair-type DNA synthesis. As previous studies have shown ATP stimulates this DNA synthesis; we studied the mechanism of the ATP effect by analyzing the kinetics of nucleotide incorporation at various dNTP concentrations. The V values of the DNA repair synthesis rise with increasing dose (0-50 Gy); nonirradiated cells showed a negligible nucleotide incorporation. The apparent Michaelis constant KM for dNTP in the assay was 83-143 microM and the value was much higher than for a DNA polymerase reaction in vitro. ATP stimulated the DNA synthesis with concomitant decrease of KM yet unchanged V values. Similar results were obtained with a rec BC strain. We propose that the ATP effect is due to a greater affinity of dNTPs to the DNA polymerase, possibly by a stabilisation of the structural integrity of the complex DNA with repair enzymes. Activation of exonucleases by ATP could be excluded. Addition of NAD to the reaction mixture inhibits the DNA synthesis possibly by activation of ligase which closes the nicks in the DNA strand.

Adenosine Triphosphate↗
PubMed2004

ABL-fusion oncoproteins activate multi-pathway of DNA repair: role in drug resistance?

Chromosomal translocations of tyrosine kinase c-ABL gene from chromosome 9 may generate oncogenic kinases exhibiting constitutive tyrosine kinase activity. Recently, we have shown that ABL-fusion oncogenic tyrosine kinases, BCR/ABL and TEL/ABL, specific to hematopoietic malignances, induced resistance to DNA-damaging agents. To elucidate the role of DNA repair in this phenomenon we examined the capacity of murine BaF3 lymphoid cells and their TEL/ABL-transformed counterparts to repair DNA lesions caused by gamma- and UV-radiations and the anti-cancer drug, idarubicin. TEL/ABL-transformed cells displayed resistance to these DNA damaging agents as evaluated by MTT assay and the survival advantage was associated with an accelerated kinetics of DNA repair as measured by the alkaline comet assay. Deoxyribonucleosides (dNTPs) supplementation of the repair medium further stimulated DNA repair and the effect was specific to the DNA damage agent used in the experiment but only the transformed cells displayed this feature. A variety of damages induced imply the multi-pathway of DNA repair involved. We also examined the capability of BCR/ABL-fusion to modulate the repair of oxidative lesions, considered as a major side effect of various anti-cancer drugs including idarubicin and radiation. Employing the free radical scavenger alpha-phenyl-N-tert-butyl nitrone (PBN, a spin trap) and DNA repair enzymes: endonuclease III (EndoIII) that nicks DNA at sites of oxidized bases, we found that BCR/ABL-transformed cells repaired oxidative DNA lesions more effectively than control cells. Our results suggest, that oncogenic ABL-dependent stimulation of DNA repair may contribute to the cell resistance to genotoxic treatment.

Animals↗
PubMed1982

Effects of DNA polymerase inhibitors on replicative and repair DNA synthesis in ultraviolet-irradiated HeLa cells.

Aphidicolin specifically inhibits eukaryotic DNA polymerase alpha, while 2',3'-dideoxythymidine 5'-triphosphate (d2TTP) inhibits DNA polymerase beta and gamma but not alpha. 1-beta-D-Arabinofuranosylcytosine 5'-triphosphate (araCTP) inhibits both DNA polymerase alpha and beta although to a different extent. Here we measured the effects of these inhibitors on repair DNA synthesis of U.V.-irradiated HeLa cells by two different methods. Firstly, aphidicolin, 1-beta-D-arabinofuranosylcytosine (araC, a precursor of araCTP) and 2',3'-dideoxythimidine (d2Thd, a precursor of d2TTP) were added directly to the culture medium. In this case, aphidicolin and araC strongly inhibited replicative DNA synthesis of HeLa cells, and they also inhibited repair synthesis after U.V.-irradiation but to a much lesser extent. In contrast, high concentrations of d2Thd inhibited repair DNA synthesis to a higher extent than replicative DNA synthesis. Secondly, the active form of inhibitor, d2TTP, was microinjection directly into cytoplasm or nuclei or U.V.-irradiated HeLa cells. Microinjection of d2TTP effectively inhibited repair synthesis. The microinjection of d2TTP, into either cytoplasm or nucleus, strongly inhibited replicative synthesis. These results might indicate that multiple DNA polymerases are involved in repair synthesis as well as in replicative synthesis.

Aphidicolin↗
PubMed1997

The DNA repair protein O6-methylguanine-DNA methyltransferase protects against skin tumor formation induced by antineoplastic chloroethylnitrosourea.

Chloroethylnitrosoureas (CNUs) are being used in the therapy of various neoplastic diseases, including skin cancer. Because secondary tumor formation is a serious threat in chemotherapy with these drugs, we explored whether and to what extent the DNA repair protein DNA-O6-methylguanine:protein-L-cysteine S-methyltransferase (MGMT) protects against CNU-induced tumors. We made use of transgenic mice overexpressing human MGMT in their skin and the initiation-promotion protocol on treatment with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine) that is representative of CNUs. ACNU applied topically as a single low dose to the dorsal skin was highly effective in tumor induction in nontransgenic mice, whereas in cytokeratin MGMT transgenic mice, tumor formation was remarkably reduced. ACNU-induced skin tumors harbored mutations in the c-Ha-ras gene in both groups of mice. The results provide clear evidence that MGMT exerts protection against CNU-induced cancer. Our data also indicate that O6-chloroethylguanine, which is repaired by MGMT, is a main precarcinogenic CNU-induced DNA lesion.

Animals↗
PubMed2006

Cross-linking of the human DNA repair protein O6-alkylguanine DNA alkyltransferase to DNA in the presence of 1,2,3,4-diepoxybutane.

1,2,3,4-Diepoxybutane (DEB) is a key carcinogenic metabolite of the important industrial chemical 1,3-butadiene. DEB is a bifunctional alkylating agent capable of reacting with DNA and proteins. Initial DNA alkylation by DEB produces N7-(2'-hydroxy-3',4'-epoxybut-1'-yl)-guanine monoadducts, which can react with another nucleophilic site to form cross-linked adducts. A recent report revealed a strong correlation between cellular expression of the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) and the cytotoxic and mutagenic activity of DEB, suggesting that DEB induces AGT-DNA cross-links (Valadez, J. G., et al. (2004) Activation of bis-electrophiles to mutagenic conjugates by human O6-alkylguanine-DNA alkyltransferase. Chem. Res. Toxicol. 17, 972-982). The purpose of our study was to analyze the formation and structures of DEB-induced AGT-DNA conjugates and to identify specific amino acid residues within the protein involved in cross-linking. DNA-protein cross-link formation was detected by SDS-PAGE when 32P-labeled double-stranded oligodeoxynucleotides were exposed to DEB in the presence of either wild-type hAGT or a C145A hAGT mutant. Capillary HPLC-electrospray ionization mass spectrometry (ESI-MS) analysis of hAGT that had been treated with N7-(2'-hydroxy-3',4'-epoxybut-1'-yl)-deoxyguanosine (dG monoepoxide) revealed the ability of the protein to form either one or two butanediol-dG cross-links, corresponding to mass shifts of +353 and +706 Da, respectively. HPLC-ESI+ -MS/MS sequencing of the tryptic peptides obtained from dG monoepoxide-treated protein indicated that the two cross-linking sites were the alkyl acceptor site, Cys145, and a neighboring active site residue, Cys150. The same two amino acid residues of hAGT became covalently cross-linked to DNA following DEB treatment. Modification of Cys145 was further confirmed by HPLC-ESI+ -MS/MS analysis of dG monoepoxide-treated synthetic peptide GNPVPILIPCHR which represents the active site tryptic fragment of hAGT (C = Cys145). The replacement of the catalytic cysteine residue with alanine in the C145A hAGT mutant abolished DEB-induced cross-linking at this site, while the formation of conjugates via neighboring Cys150 was retained. The exact chemical structure of the cross-linked lesion was established as 1-(S-cysteinyl)-4-(guan-7-yl)-2,3-butanediol by HPLC-ESI+ -MS/MS analysis of the amino acids resulting from the total digestion of modified proteins analyzed in parallel with an authentic standard. AGT-DNA cross-linking is a likely mechanism of DEB-mediated cytotoxicity in cells expressing this important repair protein.

Alkylating Agents↗
PubMed2004

Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs.

The DNA repair proteins poly(ADP-ribose) polymerase-1 (PARP-1), Ku86, and catalytic subunit of DNA-PK (DNA-PKcs) have been involved in telomere metabolism. To genetically dissect the impact of these activities on telomere function, as well as organismal cancer and aging, we have generated mice doubly deficient for both telomerase and any of the mentioned DNA repair proteins, PARP-1, Ku86, or DNA-PKcs. First, we show that abrogation of PARP-1 in the absence of telomerase does not affect the rate of telomere shortening, telomere capping, or organismal viability compared with single telomerase-deficient controls. Thus, PARP-1 does not have a major role in telomere metabolism, not even in the context of telomerase deficiency. In contrast, mice doubly deficient for telomerase and either Ku86 or DNA-PKcs manifest accelerated loss of organismal viability compared with single telomerase-deficient mice. Interestingly, this loss of organismal viability correlates with proliferative defects and age-related pathologies, but not with increased incidence of cancer. These results support the notion that absence of telomerase and short telomeres in combination with DNA repair deficiencies accelerate the aging process without impacting on tumorigenesis.

Aging, Premature↗
PubMed2002

Expression and mutation analyses of P53R2, a newly identified p53 target for DNA repair in human gastric carcinoma.

p53R2, a recently identified putative tumor suppressor located at 8q23.1, encodes a protein with striking similarity to a small subunit of ribonucleotide reductase. p53R2 is directly induced by wild-type p53 and involved in the p53 checkpoint for repair of damaged DNA, raising the possibility that mutational inactivation of p53R2 may contribute to the development and progression of human malignancies. To explore the p53R2's candidacy for a suppressor in gastric tumorigenesis, we examined the expression and mutation status of p53R2 in 166 gastric specimens including 90 primary adenocarcinomas and 15 cell lines. In response to genotoxic damages, p53R2 transcription was clearly activated in wild-type but not mutant-type p53-carrying cells while basal expression of p53R2 in undamaged cells showed no association with the mutational status of p53. Host cell reactivation assay revealed that p53R2 enhances DNA repair efficiency and plays a role in the p53-mediated repair of damaged DNA, whereas no significant effect of p53R2 on cell growth and apoptosis was detected in flow cytometry and [(3)H]thymidine incorporation assays. p53R2 transcript was expressed in all normal and tumor tissues and its expression levels were not significantly different between normal and malignant carcinoma tissues. p53R2 expression showed no correlation with stage, grade and histological types of tumors. Moreover, no tumor-specific reduction of p53R2 was detected in 30 matched sets. Mutational analysis of p53R2 in 105 carcinomas including 15 cell lines also failed to detect any evidences for genomic deletion or somatic mutations leading to amino acid substitutions or frameshift whereas 31% (28 of 90) of the same primary tumors showed p53 alterations. Whereas 82% (23 of 28) of the mutant p53-carrying primary tumors expressed abnormally low p21(Waf1), no association of p53R2 expression with the p53 status was recognized, suggesting that basal transcription of p53R2 is regulated through the p53-independent mechanism. Collectively, our study indicates that although p53R2 is induced in a p53-dependent manner and involved the p53-mediated DNA repair in gastric epithelial cells, it is not a critical target of genetic inactivation in gastric tumorigenesis.

Adenocarcinoma↗
PubMed2005

Contact with host cells induces a DNA repair system in pathogenic Neisseriae.

DNA repair systems play a major role in maintaining the integrity of bacterial genomes. Neisseria meningitidis, a human pathogen capable of colonizing the human nasopharynx, possesses numerous DNA repair genes but lacks inducible DNA repair systems such as the SOS response, present in most bacteria species. We recently identified a set of genes upregulated by contact with host cells. An open reading frame having high homology with the small subunit of Escherichia coli exonuclease VII (xseB) belongs to this regulon. The increased sensitivity of a mutant in this coding sequence to UV irradiation, alkylating agent and nalidixic acid demonstrates the participation of this gene in meningococcal DNA repair. In addition, the upregulation of the transcription of this open reading frame upon interaction of N. meningitidis with host cells increased not only the bacterial ability to repair its DNA but also the rate of phase variation by frameshifting. Together these data demonstrate that N. meningitidis possesses an inducible DNA repair system that might be used by the bacteria to adapt to its niches when it is colonizing a new host.

Bacterial Proteins↗
PubMed2002

Immunological disorders and DNA repair.

Cellular DNA continuously incurs damage and a range of damage response mechanisms function to maintain genomic integrity in the face of this onslaught. During the development of the immune response, the cell utilises three defined processes, V(D)J recombination, class switch recombination and somatic hypermutation, to create genetic diversity in developing T and B cells. Curiously, the damage response mechanisms employed to maintain genomic stability in somatic cells have been exploited and adapted to help generate diversity during immune development. As a consequence of this overlap, there is mounting evidence that disorders attributable to impaired damage response mechanisms display associated immunodeficiency. Since double strand breaks (DSB) are created during at least two of the mechanisms used to create immunoglobulin diversity, namely V(D)J recombination and class switch recombination, it is not surprising that disorders associated with defects in the response to double strand breaks are those most associated with immunodeficiency. Here, we review the steps involved in the generation of genetic diversity during immune development with a focus on the damage response mechanisms employed and then consider human immunodeficiency disorders associated with impaired damage response mechanisms.

Chromosome Breakage↗
PubMed1989

Perturbation of DNA tertiary structure by physical and chemical carcinogens: effects on DNA repair processes.

DNA within the cell is organized into higher-order structures characterized by negative supercoiling. Supercoiling is a property of any DNA molecule lacking ends capable of rotation. Parameters defining the properties of supercoiled DNA are significant for the description of the reactive state of DNA molecules. We have investigated whether physical and chemical DNA modifying agents alter the parameters describing the DNA tertiary structure. The variations in DNA tertiary structure of partially relaxed topoisomers obtained from plasmid DNA have been studied by one dimensional agarose gel electrophoresis, a technique allowing the measurement of alterations in the degree of supercoiling equivalent to fractions of superhelical turns. Unwinding angles of 8.5 degrees for pyrimidine dimers and of 8.5 degrees for acetyl-4-hydroxyaminoquinoline-I-oxide (Ac-4-HAQO) adducts have been determined by titrating for each topoisomers the number of damaged sites necessary to reduce the superhelical turns by one. Analogous unwinding was observed for topoisomers obtained from in vivo irradiated plasmid DNA. We have also shown that local alterations in DNA structure caused by UV irradiation inhibit bacterial type I DNA topoisomerases. In addition, we have demonstrated that E. coli mutants lacking DNA topoisomerase I are sensitive to UV light. The pronounced inhibition of DNA synthesis as well as the chromosome instability observed after UV irradiation of this strain, suggest that DNA topoisomerase I might be involved in those cellular responses elicited by the proximity of damaged bases to sites of active replication.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinogens↗
PubMed2003

Promoter hypermethylation of the DNA repair gene O6-methylguanine-DNA methyltransferase is an independent predictor of shortened progression free survival in patients with low-grade diffuse astrocytomas.

The O6-methylguanine-DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. In several human neoplasms including low-grade diffuse astrocytomas, promoter hypermethylation of MGMT has been shown to correlate with an increased frequency of p53 mutation. In the present study, we analyzed MGMT promoter methylation by the methylation-specific PCR in 49 newly diagnosed WHO grade II astrocytomas and evaluated its clinical usefulness. MGMT promoter methylation was found in 21 (43%) of the 49 tumors. A tight correlation existed between MGMT methylation and p53 protein accumulation (P=0.0424). The presence of MGMT methylation was significantly associated with a shorter progression free survival (PFS) on both univariate analysis (P=0.0014) and multivariate analysis (P=0.0081). It was a more powerful determinant of the PFS than age, sex, performance status, proliferative activity, or p53 expression, and was independent of the extent of surgery. In terms of the overall survival, MGMT methylation demonstrated a prognostic utility in the univariate analysis but not in the multivariate analysis. The present findings indicate that aberrant methylation of the MGMT promoter independently augurs for an unfavorable clinical course in patients with low-grade diffuse astrocytomas. Since the presence of MGMT methylation is expected to predict an increased sensitivity to alkylating chemotherapeutic agents, earlier chemotherapy could serve to improve an unfavorable natural history in tumors with MGMT methylation.

Adult↗
PubMed1985

Differential capacities for DNA repair in Clara cells, alveolar type II cells and macrophages of rabbit lung.

The ability to repair damaged DNA was determined in different cell populations of rabbit lung cells isolated by centrifugal elutriation. DNA excision repair, measured as unscheduled DNA synthesis, was examined in in vitro confluent primary cultures. A dose dependent level of DNA excision repair was observed in alveolar type II cells after exposure to the direct acting alkylating agents N-methyl-N'-nitro-N-nitrosoguanidine, N-ethyl-N-nitrosourea and methyl methansesulphonate. Furthermore, O6-alkylguanine-DNA alkyltransferase activity was easily detectable in alveolar type II cells and alveolar macrophages. In contrast, non-ciliated (Clara) cells had 4 to 20-fold lower levels of DNA excision repair and non-detectable levels of O6-alkylguanine-DNA alkyltransferase. Uracil-DNA glycosylase activities in Clara cells and alveolar type II cells were in the same range and had 3-fold lower activity than alveolar macrophages. Our findings indicate that various lung cells differ in DNA repair capacity and may thus differ in sensitivity to some carcinogens.

Animals↗
PubMed2006

Emerging cancer therapeutic opportunities target DNA-repair systems.

DNA-damaging agents have a central role in non-surgical cancer treatment. The balance between DNA damage and repair determines the final therapeutic consequences. An elevated DNA-repair capacity in tumor cells leads to drug or radiation resistance and severely limits the efficacy of these agents. Interference with DNA repair has emerged as an important approach in combination therapy against cancer. Anticancer targets in DNA-repair systems have emerged, against which several small-molecule compounds are currently undergoing clinical trials.

Animals↗
PubMed1992

A mammalian cell line deficient in activity of the DNA repair enzyme 5-hydroxymethyluracil-DNA glycosylase is resistant to the toxic effects of the thymidine analog 5-hydroxymethyl-2'-deoxyuridine.

We isolated a mutant mammalian cell line lacking activity for the DNA repair enzyme 5-hydroxymethyluracil-DNA glycosylase (HmUra-DNA glycosylase). The mutant was isolated through its resistance to the thymidine analog 5-hydroxymethyl-2'-deoxyuridine (HmdUrd). The mutant incorporates HmdUrd into DNA to the same extent as the parent line but, lacking the repair enzyme, does not remove it. The phenotype of the mutant demonstrates that the toxicity of HmdUrd does not result from substitution of thymine in DNA by HmUra but rather from the removal via base excision of large numbers of HmUra residues in DNA. This finding elucidates a novel mechanism of toxicity for a xenobiotic nucleoside. Furthermore, the isolation of this line supports our hypothesis that the enzymatic repairability of HmUra derives not from its formation opposite adenine via the oxidation of thymine, but rather from its formation opposite guanine as a product of the oxidation and subsequent deamination of 5-methylcytosine.

Animals↗