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At least 163 records · Page 9Linked to original sources
PubMed1989

Cloning of Salmonella typhimurium DNA encoding mutagenic DNA repair.

Mutagenic DNA repair in Escherichia coli is encoded by the umuDC operon. Salmonella typhimurium DNA which has homology with E. coli umuC and is able to complement E. coli umuC122::Tn5 and umuC36 mutations has been cloned. Complementation of umuD44 mutants and hybridization with E. coli umuD also occurred, but these activities were much weaker than with umuC. Restriction enzyme mapping indicated that the composition of the cloned fragment is different from the E. coli umuDC operon. Therefore, a umu-like function of S. typhimurium has been found; the phenotype of this function is weaker than that of its E. coli counterpart, which is consistent with the weak mutagenic response of S. typhimurium to UV compared with the response in E. coli.

Cloning, Molecular↗
PubMed1989

[DNA repair and drug resistance: enhancement of the effects of anticancer agents by DNA repair inhibitors].

Recently, it has been revealed that anticancer effects are increased by the inhibition of DNA repair of cancer cells. Methylxanthine is the drug which block DNA repair. In this study we discussed the combined effects of CDDP and caffeine or pentoxifylline using human osteosarcoma cells (OST strain). When 2 mM caffeine was added before 1 hr exposure of CDDP or caffeine and CDDP was added simultaneously for 1 hr, no synergistic effect was shown. On the other hand, marked synergistic growth inhibition was observed when caffeine or pentoxifylline was added continuously after 1 hr exposure of CDDP. The addition of caffeine from 24 hr to 48 hr after 1 hr exposure of CDDP also showed synergistic effects as the doubling time of OST cells was about 30 hrs. Further more we treated three patients with advanced osteosarcomas by the combination of CDDP, ADM, and caffeine (p.o.) or that of CDDP and caffeine. A nine-year-old boy with multicentric osteosarcoma treated by the combination of CDDP, ADM, and caffeine showed partial response, and caffeine did not increase the side effects of anticancer agents. Hence the study on overcoming drug resistance by the inhibition of DNA repair will be promising.

Adolescent↗
PubMed1995

DNA repair proteins.

DNA repair proteins act to correct mutagenic and toxic DNA damage, which can lead to cancer, aging and death. These proteins and their mechanisms of action have been found to be widely conserved between species, often from bacteria to man. Structural and biochemical studies on several bacterial enzymes involved in direct reversal and base excision repair have provided insights into the molecular basis of the recognition of damaged DNA and have also highlighted the novel roles that transition metals play in DNA repair.

Amino Acid Sequence↗
PubMed1999

Nonradioactive detection of DNA repair synthesis.

DNA repair is essential for the surveillance and maintenance of the integrity of the genome in response to various insults that damage DNA. The development of cell-free repair systems using radiolabeled nucleotide to monitor repair synthesis of exogenously introduced damaged-plasmid DNA has enabled the analysis of specific proteins required for repair synthesis. However, the hazards and the burgeoning cost of using radioisotopes have become significant factors in the laboratory. We describe here the use of digoxigenin-dUTP in place of radioactivity in a nonradioactive cell-free repair assay to detect DNA repair.

Animals↗
PubMed2005

Error-prone DNA repair and translesion DNA synthesis. II: The inducible SOS hypothesis.

Evelyn Witkin hypothesized in 1967 that bacterial cell division is controlled by a repressor which, like the lambda repressor, is inactivated by a complex process that starts with the presence of replication-blocking lesions in the DNA. She further suggested that this might not be the only cellular function to show induction by DNA damage. Three years later, Miroslav Radman, in a privately circulated note, proposed that one such function might be an inaccurate (mutation-prone) DNA polymerase under the control of the recA and lexA genes. Thus was born the SOS hypothesis.

DNA Repair↗
PubMed1984

Comparative enzymology of ultraviolet-induced DNA repair synthesis and semiconservative DNA replication in permeable diploid human fibroblasts.

In nongrowing mammalian cells, DNA repair synthesis following irradiation with high doses of UV is almost totally inhibited by aphidicolin, an agent specific for DNA polymerase alpha, and presumably is mediated by that polymerase. In this paper, several enzymologic characteristics of DNA repair synthesis induced in permeable confluent diploid human fibroblasts by high doses of UV have been examined and compared with corresponding features of semiconservative DNA replication, a process which is also mediated by polymerase alpha. Inhibition of UV-induced repair synthesis required doses of aphidicolin about 20-fold higher than those needed to inhibit replication, even when the two processes were studied at identical salt and nucleotide concentrations. As is the case for replication, inhibition of UV-induced repair synthesis by aphidicolin is competitive with dCTP. The apparent Ki values for aphidicolin of the two processes are similar, 0.2 microM for repair synthesis and 0.1 microM for semiconservative replication. In contrast, the apparent Km values for dCTP are very different, 0.17 microM for repair synthesis and about 2 microM for replication. The apparent Km values for all four deoxyribonucleoside triphosphates varied together are also very different, 0.07 microM for repair and 30 microM for replication. These results suggest that either UV-induced DNA repair synthesis and semiconservative replication are mediated by two different aphidicolin-sensitive DNA polymerases or the two functions are performed by a single polymerase (e.g. polymerase alpha) which, as a result of accessory proteins or other factors, acquires very different enzymologic characteristics.

Aphidicolin↗
PubMed1995

Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair.

Eukaryotic DNA polymerase beta (pol beta) can catalyze DNA synthesis during base excision DNA repair. It is shown here that pol beta also catalyzes release of 5'-terminal deoxyribose phosphate (dRP) residues from incised apurinic-apyrimidinic sites, which are common intermediate products in base excision repair. The catalytic domain for this activity resides within an amino-terminal 8-kilodalton fragment of pol beta, which comprises a distinct structural domain of the enzyme. Magnesium is required for the release of dRP from double-stranded DNA but not from a single-stranded oligonucleotide. Analysis of the released products indicates that the excision reaction occurs by beta-elimination rather than hydrolysis.

Animals↗
PubMed1982

Age dependency of DNA repair in rats after DNA damage by carcinogens.

Damage to DNA seems to be an important cause of cancer and to play a role in aging. Much of this damage results from the action of chemical agents in the environment. These chemicals provide a chance to study DNA repair mechanisms and to construct a model for the investigation of changes in repair with aging. To damage the DNA of male Sprague-Dawley rats aged 6, 22-24 and 24-26 months, three carcinogens were used: N-methyl-N-nitrosourea (MNU), methyl methane sulfonate (MMS) and N,N-dimethyl-nitrosamine (DMN). DNA repair was measured as unscheduled DNA synthesis (UDS) in ten (MNU and DMN) and five (MMS) different organs. MNU and MMS react with DNA without being first metabolized and show a higher UDS in lower concentration than DMN which is metabolized enzymatically prior to the reaction. This result suggests that MNU and MMS produce more damage in the DNA. There are distinct differences in the spleen, lung, liver, kidney and heart in young animals as well as in the tissues of the kidney and the duodenum in old rats. Clearly we can see a reduction of UDS in the old as compared to the young animals after damage by MNU in the skin, lung, brain and heart, by MMS in the heart and liver, and by DMN in the kidney, duodenum, lung and liver, and by all three mutagens in the spleen and testes. These results confirm those obtained after damaging DNA by means of gamma- and UV-irradiation.

Aging↗
PubMed1978

Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Analysis of DNA repair induced by carcinogenic K-region epoxides and 1,2,3,4-diepoxybutane.

Ether-permeabilized (nucleotide-permeable) Escherichia coli cells exhibited DNA excision repair when exposed to the following carcinogenic K-region epoxides: 7-methyl- and 7,12-dimethyl-benz[a]anthracene-5,6-oxide, chrysene-5,6-oxide and benzo[a]pyrene-4,5-oxide. This DNA excision repair was missing in uvr A and uvr B mutant cells. The K-region epoxide phenanthrene-9,10-oxide was ineffective in all E. coli strains tested. In contrast to the K-region epoxides which where found active only in wild type cells, 1,2,3,4-diepoxybutane and the 6,7-epoxides of the tumor promoter TPA (12-O-tetradecanoyl-phorbol-13-acetate) elicited DNA repair in uvrA, uvrB mutant cells as well. Enzymic activities catalyzing particular repair steps were identified by determining a) repair polymerization and b) size reduction of denatured DNA. A) An easily quantifiable effect in E. coli wild type cells was epoxide-induced repair polymerization. None of the K-region epoxides tested stimulated DNA repair synthesis in uvrA, uvrB mutant cells, indicating that the uvrA-, uvrB-controlled UV-endonuclease initiated excision repair by cleaving epoxide-damaged DNA. 1,2,3,4-Diepoxybutane and the TPA-6,7-oxides induced DNA repair polymerization in uvr-deficient cells, although to a lesser extent than in wild type cells, suggesting the involvement of uvr-independent incision steps. None of the epoxides induced repair polymerization in a mutant (polA107) lacking the 5'--3'exonucleolytic activity of DNA polymerase I (exonuclease VI). The absence of any repair polymerization in the polA107 mutant indicates that the exonuclease VI plays a central role in removing epoxide-damaged nucleotides. As evidenced by greatly reduced levels of repair polymerization measured in polA1 cells, DNA polymerase I was the main polymerizing enzyme. b) As a consequence of treatment with 7-methyl-benz[a]anthracene-5,6-oxide, DNA from wild type cells, contrary to uvrA mutant cells, showed size reduction after denaturation and sedimentation in alkaline sucrose gradients. This is explained by repair-specific endonucleolytic cleavage of damaged DNA. The incision required the presence of ATP indicating that functional UV-endonuclease needs ATP as a cofactor.

Carcinogens↗
PubMed1975

Human diseases with genetically altered DNA repair processes.

DNA repair of single-strand breaks (produced by ionizing radiation) and of base damage (produced by ultraviolet (UV) light) are two repair mechanisms that most mammalian cells possess. Genetic defects in these repair mechanisms are exemplified by cells from the human premature-aging disease, progeria, which fail to rejoin single-strand breaks, and the skin disease, xeroderma pigmentosum (XP), which exhibits high actinic carcinogenesis and involves failure to repair base damage. In terms of the response of XP cells, many chemical carcinogens can be classified as either X-ray-like (i.e., they cause damage that XP cells can repair) or UV-like (i.e., they cause damage that XP cells cannot repair). The first group contains some of the more strongly carcinogenic chemicals (e.g., alkylating agents). XP occurs in at least two clinical forms, and somatic cell hybridization indicates at least three complementation groups. In order to identify cell lines from various different laboratories unambiguously, a modified nomenclature of XP lines is proposed.

Carcinogens↗
PubMed1985

DNA-mediated transfer of a human DNA repair gene that controls sister chromatid exchange.

The Chinese hamster cell line mutant EM9, which has a reduced ability to repair DNA strand breaks, is noted for its highly elevated frequency of sister chromatid exchange, a property shared with cells from individuals with Bloom's syndrome. The defect in EM9 cells was corrected by fusion hybridization with normal human fibroblasts and by transfection with DNA from hybrid cells. The transformants showed normalization of sister chromatid exchange frequency but incomplete correction of the repair defect in terms of chromosomal aberrations produced by 5-bromo-2'-deoxyuridine.

DNA↗
PubMed2002

Does reduced DNA repair capacity play a role in HIV infection and progression in the lymphocytes of opiate addicts?

Opiate use in vivo and in vitro reduces the ability of human peripheral lymphocytes to repair DNA damage caused by both the physical and chemical mutagens that produce single-strand adducts. This decrease in repair leads to increased genetic damage to the individual cell as measured by cytogenetic damage, including sister chromatid exchanges and formation of micronuclei. The expected consequences of this increase in damage can also be established by increases in host cell mutation rate and rate of apoptosis. The effect of this increase in genetic damage can be expected to have significant consequences for HIV-1 or simian immunodeficiency virus infecting those lymphocytes. For example, DNA damaging agents have long been known to induce lentiviral growth and propagation, and this has been found to be true for HIV-1 following ultraviolet light treatment of lymphocytes. However, to date, no one has fully explored the consequences of increased host mutation rate on HIV growth and maintenance. Recent reports have demonstrated the role of viral mutation in such key physiologic processes as resistance to highly active antiretroviral therapy (HAART). Beyond the effects of random mutations in the viral genome, specific mutations in the HIV-1 transcriptase and protease lead to increased accumulation of mutant viruses and the gradual failure of HAART. It therefore remains to be tested whether changes in host cell mutation rate will also predict changes in susceptibility to drug therapy. This also leads to questions about whether the higher rate of viral mutation in HIV-infected drug addicts might be the basis for higher rates of neuroAIDS in this population. It would be attractive to speculate that the increase in the heterogeneity of the virus in addicts produces mutants with a greater capacity to attack neuronal tissue and a high affinity to replicate there.

Cocaine↗
PubMed1989

DNA repair deficiency for alkylation damage in cells from Alzheimer's disease patients.

We have shown that fibroblasts, lymphocytes and lymphoblasts from patients with Alzheimer's disease (AD) are deficient in the repair of DNA damage induced by the alkylating agents methylmethane sulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Unscheduled DNA synthesis and alkaline elution studies of DNA repair using human skin fibroblasts obtained from patients coming to autopsy have shown that the cells from autopsy confirmed cases of AD have lower levels of DNA repair synthesis after exposure to varying concentrations of either MMS or MNNG. Lymphoblasts derived from individuals with dominantly inherited AD have also been used to study DNA repair. Alkaline elution analysis of DNA repair after exposure to 200 uM MMS or 6 uM MNNG indicates that there is significantly less repair in the lymphoblasts from AD patients. When healthy control cell lines repaired and cell lines from AD patients were exposed to MMS or MNNG respectively significantly less repair occurred in the AD cells. After studying five at risk individuals results indicate that cell lines from two of these people have low levels of DNA repair and three lines have normal repair. These findings support the hypothesis of a DNA repair deficiency in familial AD. Monocytes from healthy control subjects and putative AD patients were analyzed for mutant frequency and DNA repair capacity. Results of unscheduled DNA synthesis experiments using monocytes from 7 healthy controls and 9 presumed AD patients indicates that there is a decreased ability of AD cells to repair MMS and MNNG induced DNA damage.

Alkylating Agents↗
PubMed2001

DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study.

Individuals differ widely in their ability to repair DNA damage, and DNA-repair deficiency may be involved in modulating cancer risk. In a case-control study of 124 bladder-cancer patients and 85 hospital controls (urological and non-urological), 3 DNA polymorphisms localized in 3 genes of different repair pathways (XRCC1-Arg399Gln, exon 10; XRCC3-Thr241Met, exon 7; XPD-Lys751Gln, exon 23) have been analyzed. Results were correlated with DNA damage measured as (32)P-post-labeling bulky DNA adducts in white blood cells from peripheral blood. Genotyping was performed by PCR-RFLP analysis, and allele frequencies in cases/controls were as follows: XRCC1-399Gln = 0.34/0.39, XRCC3-241Met = 0.48/0.35 and XPD-751Gln = 0.42/0.42. Odds ratios (ORs) were significantly greater than 1 only for the XRCC3 (exon 7) variant, and they were consistent across the 2 control groups. XPD and XRCC1 appear to have no impact on the risk of bladder cancer. Indeed, the effect of XRCC3 was more evident in non-smokers [OR = 4.8, 95% confidence interval (CI) 1.1-21.2]. XRCC3 apparently interacted with the N-acetyltransferase type 2 (NAT-2) genotype. The effect of XRCC3 was limited to the NAT-2 slow genotype (OR = 3.4, 95% CI 1.5-7.9), suggesting that XRCC3 might be involved in a common repair pathway of bulky DNA adducts. In addition, the risk of having DNA adduct levels above the median was higher in NAT-2 slow acetylators, homozygotes for the XRCC3-241Met variant allele (OR = 14.6, 95% CI 1.5-138). However, any discussion of interactions should be considered preliminary because of the small numbers involved. Our results suggest that bladder-cancer risk can be genetically modulated by XRCC3, which may repair DNA cross-link lesions produced by aromatic amines and other environmental chemicals.

Aged↗
PubMed1995

E2F-1 and a cyclin-like DNA repair enzyme, uracil-DNA glycosylase, provide evidence for an autoregulatory mechanism for transcription.

The cell cycle-dependent transcription factor, E2F-1, regulates the cyclin-like species of the DNA repair enzyme uracil-DNA glycosylase (UDG) gene in human osteosarcoma (Saos-2) cells. We demonstrate, through the deletion of the human UDG promoter sequences, that expression of E2F-1 activates the UDG promoter through several E2F sites. The major putative downstream site for E2F, located in the first exon, serves as a target for E2F-1/DP1 complex binding in vitro. We also provide evidence for the functional relationship between the cyclin-like UDG gene product and E2F. High levels of UDG expression in a transient transfection assay result in the down-regulation of transcriptional activity through elements specific for E2F-mediated transcription. Overexpression of UDG in Saos 2 cells was observed to delay growth late in G1 phase and transiently arrest these cells from progressing into the S phase. This hypothetical model integrates one mechanism of DNA repair with the cell cycle control of gene transcription, likely through E2F. This implicates E2F as a multifunctional target for proteins and enzymes, possibly, responsive to DNA damage through the negative effect of UDG on E2F-mediated transcriptional activity.

Antigens, CD↗
PubMed1987

Isolation of a herpes simplex virus cDNA encoding the DNA repair enzyme uracil-DNA glycosylase.

Activity of the DNA repair enzyme uracil-DNA glycosylase has been shown to increase in herpes simplex virus type 2 (HSV-2)-infected cells. When mRNA derived from either HSV-1- or HSV-2-infected HeLa S3 cells was translated in an in vitro translation system, significant uracil-DNA glycosylase activity could be detected in the lysate. This activity was specific for the removal of uracil from DNA. Lysates from in vitro translation of mRNA derived from uninfected HeLa cells did not contain measurable glycosylase activity. A cDNA library was constructed with mRNA derived from HSV-2-infected cells 10 h postinfection. Pooled isolates from this library were used in hybrid-arrest and in vitro translation reactions to isolate a uracil-DNA glycosylase-specific cDNA. In vitro translation of hybrid-selected RNA, by using this cDNA, produced glycosylase activity in the lysate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radiolabeled products from this translation reaction showed a protein component with a molecular weight of 39,000. This is consistent with the molecular weight determinations of the purified glycosylase enzyme derived from either uninfected or HSV-infected HeLa cells. Northern (RNA blot) analysis of HSV-derived RNA, by using the glycosylase cDNA as a probe, revealed five overlapping transcripts of 3.4, 2.8, 2.4, 1.7, and 1.0 kilobases. Southern analysis indicated that the DNA sequence encoding the HSV-specific uracil-DNA glycosylase was located between 0.065 and 0.08 map units on the prototypic arrangement of the HSV genome.

DNA↗
PubMed2006

Neuroanatomical mapping of DNA repair and antioxidative responses in mouse brain: Effects of a single dose of MPTP.

The primary objective of this study was to map the normal distribution of the base excision enzyme oxyguanosine glycosylase (OGG1) across mouse-brain regions as a prelude to assessing the effects of various neurotoxicants, ranging from highly selective molecules like MPTP to more global toxic agents. This research is based on the hypothesis that regional brain vulnerability to a toxicant is determined, in part, by variation in the intrinsic capacity of cellular populations to successfully repair oxidative DNA damage. After mapping the normal distributions of OGG1 and superoxide dismutase (SOD) across 44 loci dissected from mouse brain, MPTP, a mitochondrial toxicant with selective dopamine (DA) neuron cytotoxicity was used to elicit focal oxidative stress and DNA repair responses. A single dose of MPTP (20mg/kg, i.p.) elicited time- and region-dependent changes in both SOD and OGG1, with early increases in DNA repair and anti-oxidant activities throughout all regions of brain. In some sampled loci, notably the substantia nigra (SN) and hippocampus, the heightened DNA repair and antioxidant responses were not maintained beyond 48h. Other loci from cerebellum, cerebral cortex and pons maintained high levels of activity up to 72h. Levels of dopamine (DA) were decreased significantly at all time points and remained below control levels in nigro-striatal and mesolimbic systems (ventral tegmental area and nucleus accumbens). Assessment of apoptosis by TUNEL staining revealed a significant increase in number of apoptotic nuclei in the substantia nigra at 72h and not in other loci. The marked degree of apoptosis that became evident in SN at 72h was associated with large decreases in SOD and DNA repair activity at that locus. In conclusion, MPTP elicited global effects on DNA repair and antioxidant activity in all regions of brain, but the most vulnerable loci were unable to maintain elevated DNA repair and antioxidant responses.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗