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Results for “DNA Repair”

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At least 253 records · Page 14Linked to original sources

PubMed2004

Drosophila melanogaster MNK/Chk2 and p53 regulate multiple DNA repair and apoptotic pathways following DNA damage.

We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member EIGER: Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.

Animals↗

PubMed1988

DNA repair following incorporation of 5-fluorouracil into DNA of mouse bone marrow cells.

5-Fluorouracil (FUra) was previously demonstrated to be incorporated into DNA at cytotoxic concentrations in mouse bone marrow cells. Subsequently, we showed that under these conditions FUra exhibited a time-dependent removal from DNA accompanied by a decrease in DNA strand length. In the present study we utilized hydroxyurea to inhibit semiconservative DNA synthesis while monitoring DNA repair by measuring the incorporation of [3H]dThd into double-stranded DNA (DNAds), which can be separated from DNA at the replication fork (DNAss) by benzoylated-naphthoylated-DEAE cellulose. Under these conditions we assessed DNA repair in cells that had previously been exposed for 1 h to varying cytotoxic concentrations of FUra. The results demonstrate an increase in labelling of DNAds with increasing FUra concentrations, with no appreciable increase in incorporation of label into DNAss. In conclusion, this study demonstrates that DNA repair occurs following incorporation of FUra. The failure to repair DNA damage at higher FUra concentrations may have a role in the cytotoxicity of this drug.

Animals↗

PubMed1974

Intragenomal distribution of DNA repair synthesis: repair in satellite and mainband DNA in cultured mouse cells.

DNA repair synthesis was examined in mouse satellite and mainband DNA derived from confluent Balb/c 3T3 cells damaged with ultraviolet radiation or N-acetoxy-2-acetylaminofluorene. Two different approaches were used: (i) Contact-inhibited cells were treated with hydroxyurea to reduce replicative synthesis to low levels; and (ii) bromodeoxyuridine was used to label newly replicated DNA in cells that had escaped contact inhibition. DNA was separated into mainband and satellite fractions in Ag(+)-Cs(2)SO(4) gradients. After treatment with either ultraviolet radiation or N-acetoxy-2-acetylaminofluorene, repair synthesis occurred to the same extent in mainband and satellite DNA. Repair synthesis increased over an ultraviolet radiation dose range of 30-200 erg/mm(2), and the extent of repair in the two DNA species was similar at each dose level. An analysis of the separated strands of satellite DNA from ultraviolet-irradiated cells indicated that the extent of repair is closely correlated with the availability of pyrimidines for cyclobutyl dimer formation and provided evidence that repair synthesis occurs at the site of damage. Within the precision of our experiments the results suggest that at least one group of highly repetitive, nontranslated DNA sequences is repaired to about the same extent as the rest of the genome.

Animals↗

PubMed1999

[DNA repair and apoptosis].

DNA damage induced by exo- and endogenous agents triggers two opposite mechanisms--DNA repair and programmed cell death. The latter contains a phase of DNA degradation. Both mechanisms compete for DNA as a substrate and for the cell energy supply. The interaction and competition of these processes influence the pattern of cell death (from pure apoptosis to necrosis). Synergetic and competitive relations between DNA-repair and apoptosis are reviewed.

Apoptosis↗

PubMed1988

DNA repair synthesis in mouse spermatogenesis involves DNA polymerase beta activity.

The role of DNA polymerase alpha-DNA primase complex and DNA polymerase beta in DNA replication and ultraviolet-induced DNA repair synthesis has been analyzed in mouse spermatogenesis. Autoradiographic experiments with germ cells in culture, indicating an involvement of DNA polymerase alpha and/or delta in DNA replication, and of DNA polymerase beta in DNA repair synthesis, have been confirmed by studying partially purified enzymes. These findings support the idea that, different from other biological systems, in meiotic and post meiotic male mouse germ cells DNA polymerase beta is the main DNA polymerase form needed for DNA repair.

Animals↗

PubMed2004

Functional links between transcription, DNA repair and apoptosis.

DNA damage initiates damage response pathways, cell cycle arrest and apoptosis. These processes act in a concerted fashion and remain functionally linked through mechanisms not completely understood. Programmed cell death, referred to as apoptosis, is a tightly regulated phenomenon ensuring that cells that accumulate irreversible DNA damage do not replicate. Interestingly, hyperacetylation of histone proteins, which alters transcription patterns and appears linked to DNA repair, also induces apoptosis, suggesting that aspects of chromatin modification link these very distinct processes. Modulating chromatin structure in the absence of any DNA lesions also activates key DNA damage-signalling proteins, further supporting the role of higher-order chromatin structure in mediating stress responses. This review will present an overview of the epigenetic control of eukaryotic genomes by chromatin remodelling as it pertains to DNA damage and highlight the potential role of the ING PHD proteins in linking apoptosis and DNA repair to gene transcription.

Animals↗

PubMed2006

Multiplex pyrosequencing of two polymorphisms in DNA repair gene XRCC1.

DNA repair enzymes play a pivotal role in platinum-based chemotherapy. Within the gene encoding for the base excision repair enzyme XRCC1, several nonsynonymous polymorphisms have been identified. It has been shown that the Arg399Gln single-nucleotide polymorphism results in a polymorphic enzyme that is less capable of initiating DNA repair. We developed a multiplex pyrosequence assay to simultaneously detect two nonsynonymous polymorphisms within the XRCC1 gene. Both of these polymorphisms resulted in amino acid changes: G/A in codon 399 changes Arg into Gln, and deletion of A in the second position of codon 576 results in a stopcodon. We established the frequency of these mutations in 270 patients suffering from colorectal cancer. Allele frequencies of G in second position of codon 399 and A in the second position codon 576 are 61.1 and 99.6%, respectively, in these patients. This fast and reliable method allows for simultaneous detection of the infrequent mutant C or CT alleles instead of the A deletion at codon 576. The method may be used in pharmacogenetic studies of platinum-based chemotherapy.

Colorectal Neoplasms↗

PubMed2004

Homologous recombination in Candida albicans: role of CaRad52p in DNA repair, integration of linear DNA fragments and telomere length.

Chromosomal rearrangements are common in both clinical isolates and spontaneous mutants of Candida albicans. It appears that many of these rearrangements are caused by translocations around the major sequence repeat (MSR) that is present in all chromosomes except chromosome 3, suggesting that homologous recombination (HR) may play an important role in the survival of this organism. In order to gain information on these processes, we have cloned the homologue of RAD52, which in Saccharomyces cerevisiae is the only gene required for all HR events. CaRAD52 complemented poorly a rad52 mutant of S. cerevisiae. Two null Carad52Delta/Carad52Delta mutants were constructed by sequential deletion of both alleles and two reconstituted strains were obtained by reintegration of the gene. Characterization of these mutants indicated that HR plays an essential role in the repair of DNA lesions caused by both UV light and the radiomimetic compound methyl-methane-sulphonate (MMS), whereas the non-homologous end-joining pathway (NHEJ) is used only in the absence of Rad52p or after extensive DNA damage. Repair by HR is more efficient in exponentially growing than in stationary cells, probably because a larger number of cells are in late S or G2 phases of the cell cycle (and therefore, can use a sister chromatid as a substrate for recombinational repair), whereas stationary phase cells are mainly in G0 or G1, and only can be repaired using the chromosomal homologue. In addition, CaRad52p is absolutely required for the integration of linear DNA with long flanking homologous sequences. Finally, the absence of CaRad52p results in the lengthening of telomeres, even in the presence of an active telomerase, an observation not described in any other organism. This raises the possibility that both telomerase and homologous recombination may function simultaneously at C. albicans telomeres.

Amino Acid Sequence↗

PubMed1994

Effects of DNA polymerase beta gene over-expressed in transgenic Drosophila on DNA repair and recombination.

DNA polymerase beta (pol beta) cDNA of rat fused to an enhancer-promoter region plus a poly(A) signal sequence of actin 5C gene of Drosophila (abbreviated pol beta) was transferred to the Drosophila genome. Three of four constructed transgenic strains possessing transgene pol beta on different chromosomes were studied. Levels of the pol beta transcript and those of the polymerization activity of pol beta were markedly elevated in cultured cells transfected with pol beta-bearing vectors as well as in embryos of the transgenic strains. The popular idea that DNA polymerase beta participates in DNA repair was not supported by the observation that a pair of a normal and a pol beta strain, and the other pair of a mei-9 mei-41 (DNA-repair deficient double mutations) strain and a pol beta mei-9 mei-41 strain, showed no difference in survival within each pair after treatment with ultraviolet light, methylmethane sulfonate and mitomycin C. The other idea that DNA polymerase beta participates in recombination was supported by the findings that spontaneous frequency of recombination, either meiotic or mitotic, is significantly higher in a transgenic pol beta strain than in a non-transgenic strain. The enhanced recombination frequency in the pol beta strain may, however, reflect an indirect effect of over-produced pol beta proteins on chromosomal stability. Whatever the direct effect of rat pol beta is, the transgenic pol beta flies will be useful for study of the physiological role of pol beta and the mechanism of recombination.

Animals↗

PubMed2006

New tricks for old drugs: the anticarcinogenic potential of DNA repair inhibitors.

Defective or abortive repair of DNA lesions has been associated with carcinogenesis. Therefore it is imperative for a cell to accurately repair its DNA after damage if it is to return to a normal cellular phenotype. In certain circumstances, if DNA damage cannot be repaired completely and with high fidelity, it is more advantageous for an organism to have some of its more severely damaged cells die rather than survive as neoplastic transformants. A number of DNA repair inhibitors have the potential to act as anticarcinogenic compounds. These drugs are capable of modulating DNA repair, thus promoting cell death rather than repair of potentially carcinogenic DNA damage mediated by error-prone DNA repair processes. In theory, exposure to a DNA repair inhibitor during, or immediately after, carcinogenic exposure should decrease or prevent tumorigenesis. However, the ability of DNA repair inhibitors to prevent cancer development is difficult to interpret depending upon the system used and the type of genotoxic stress. Inhibitors may act on multiple aspects of DNA repair as well as the cellular signaling pathways activated in response to the initial damage. In this review, we summarize basic DNA repair mechanisms and explore the effects of a number of DNA repair inhibitors that not only potentiate DNA-damaging agents but also decrease carcinogenicity. In particular, we focus on a novel anti-tumor agent, beta-lapachone, and its potential to block transformation by modulating poly(ADP-ribose) polymerase-1.

Anticarcinogenic Agents↗

PubMedDate not supplied

Spatial expression of a DNA repair gene, N-methylpurine-DNA glycosylase (MPG) during development in mice.

BACKGROUND: DNA repair is a crucial phenomenon that maintains the chromosome integrity of genome which are continuously damaged by endogenous and exogenous alkylating agents. If the damaged DNA is not repaired, it may lead to mutation, chromosomal aberration, aging and cancer. N-methylpurine-DNA glycosylase (MPG), a ubiquitous DNA repair enzyme, removes N-methylpurine and other damaged purines in DNA. MATERIALS AND METHODS: MPG mRNA expression was revealed at various stages of mouse development from day 7.5 p.c. (post coitum) embryo to day 400 mature adult by Northern blot hybridization or RT-PCR. RESULTS: MPG transcripts were abundant in the mouse embryo during pregnancy and in adult testis and ovary. The MPG mRNA level in the testis was low in 1-week-old mice, but the level showed its maximum among the organs tested in 4-week-old young adults. In placenta, the level of MPG mRNA continuously decreased from day 7.5 p.c. to day 17.5 p.c. CONCLUSIONS: The spatial expression of MPG gene is highly regulated. Transcription of MPG is maximum in rapidly dividing and growing tissues during development. These data suggest that an elevated rate of MPG transcription is required for DNA replication.

Animals↗

PubMed1976

The time course of DNA repair following methyl nitro-nitrosoguanidine (MNNG) treatment of p388f lymphoma cells in culture. II. DNA repair synthesis and its correlation with strand breakage.

Repair synthesis has been followed in P388F cell DNA following treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) using 5-iodo-deoxyuridine (IUdR) and [3H] thymidine combination. A pattern of repair synthesis was obtained, similar in its timing to the initial and medial stages of single-strand break formation and rejoining within the first 24 h after treatment. A higher base insertion frequency in relation to single-strand breaks occurs during the medial stage of repair. However, a fundamental problem with the use of iododeoxyuridine and [3H] thymidine ([3H] TdR) as a suitable measure of repair synthesis was encountered and a potential source of error in such experiments was observed.

Cell Line↗

PubMed2002

Hypoxia induces mitochondrial DNA damage and stimulates expression of a DNA repair enzyme, the Escherichia coli MutY DNA glycosylase homolog (MYH), in vivo, in the rat brain.

Hypoxia-associated, acutely reduced blood oxygenation can compromise energy metabolism, alter oxidant/antioxidant balance and damage cellular components, including DNA. We show in vivo, in the rat brain that respiratory hypoxia leads to formation of the oxidative DNA lesion, 8-hydroxy-2'-deoxyguanosine (oh8dG), a biomarker for oxidative DNA damage and to increased expression of a DNA repair enzyme involved in protection of the genome from the mutagenic consequences of oh8dG. The enzyme is a homolog of the Escherichia coli MutY DNA glycosylase (MYH), which excises adenine residues misincorporated opposite the oxidized base, oh8dG. We have cloned a full-length rat MYH (rMYH) cDNA, which encodes 516 amino acids, and by in situ hybridization analysis obtained expression patterns of rMYH mRNA in hippocampal, cortical and cerebellar regions. Ensuing hypoxia, mitochondrial DNA damage was induced and rMYH expression strongly elevated. This is the first evidence for a regulated expression of a DNA repair enzyme in the context of respiratory hypoxia. Our findings support the premise that oxidative DNA damage is repaired in neurons and the possibility that the hypoxia-induced expression of a DNA repair enzyme in the brain represents an adaptive mechanism for protection of neuronal DNA from injurious consequences of disrupted energy metabolism and oxidant/antioxidant homeostasis.

Animals↗

PubMed1999

DNA polymerase II (polB) is involved in a new DNA repair pathway for DNA interstrand cross-links in Escherichia coli.

DNA-DNA interstrand cross-links are the cytotoxic lesions for many chemotherapeutic agents. A plasmid with a single nitrogen mustard (HN2) interstrand cross-link (inter-HN2-pTZSV28) was constructed and transformed into Escherichia coli, and its replication efficiency (RE = [number of transformants from inter-HN2-pTZSV28]/[number of transformants from control]) was determined to be approximately 0.6. Previous work showed that RE was high because the cross-link was repaired by a pathway involving nucleotide excision repair (NER) but not recombination. (In fact, recombination was precluded because the cells do not receive lesion-free homologous DNA.) Herein, DNA polymerase II is shown to be in this new pathway, since the replication efficiency (RE) is higher in a polB+ ( approximately 0. 6) than in a DeltapolB (approximately 0.1) strain. Complementation with a polB+-containing plasmid restores RE to wild-type levels, which corroborates this conclusion. In separate experiments, E. coli was treated with HN2, and the relative sensitivity to killing was found to be as follows: wild type < polB < recA < polB recA approximately uvrA. Because cells deficient in either recombination (recA) or DNA polymerase II (polB) are hypersensitive to nitrogen mustard killing, E. coli appears to have two pathways for cross-link repair: an NER/recombination pathway (which is possible when the cross-links are formed in cells where recombination can occur because there are multiple copies of the genome) and an NER/DNA polymerase II pathway. Furthermore, these results show that some cross-links are uniquely repaired by each pathway. This represents one of the first clearly defined pathway in which DNA polymerase II plays a role in E. coli. It remains to be determined why this new pathway prefers DNA polymerase II and why there are two pathways to repair cross-links.

DNA Polymerase II↗

PubMed1989

Interactions of the RAD7 and RAD23 excision repair genes of Saccharomyces cerevisiae with DNA repair genes in different epistasis groups.

The RAD7 and RAD23 genes of S. cerevisiae affect the efficiency of excision repair of UV-damaged DNA. We have examined the UV survival of strains carrying the rad7 and rad23 deletion mutation in combination with deletion mutations in genes affecting different DNA repair pathways. As expected, the rad7 delta and rad23 delta mutations interact epistatically with the excision repair defective rad1 delta mutation, and synergistically with the rad6 delta and rad52 delta mutations that affect the postreplication repair and recombinational repair pathways, respectively. However, the rad7 delta rad6 delta and the rad23 delta rad6 delta mutants exhibit the same level of UV sensitivity as the rad1 delta rad6 delta mutant. This observation is of interest since, in contrast to the rad7 delta or the rad23 delta mutations, the rad1 delta mutant is very UV sensitive and highly excision defective. This observation suggest that RAD6 and RAD7 and RAD23 genes complete for the same substrate during DNA repair.

DNA Repair↗

PubMed1986

Inducible DNA repair in microbes.

DNA damage can be removed, or tolerated by altered recombination and DNA replication. Often synthesis of extra DNA repair proteins is induced by DNA damage.

DNA Damage↗

PubMed1990

Degradation of DNA and structure-activity relationship between bleomycins A2 and B2 in the absence of DNA repair.

The contribution of DNA repair to the net number of DNA breaks produced during chemical degradation of DNA was determined by using temperature-sensitive mutant cells deficient in ATP-dependent DNA ligase [poly(deoxyribonucleotide):poly(deoxyribonucleotide) ligase, EC 6.5.1.1]. In a very sensitive assay for determining lesions introduced into Saccharomyces cerevisiae DNAs, 2-14C- and 6-3H-prelabeled DNAs from ligase-proficient and ligase-deficient cells were sedimented together through precalibrated, isokinetic alkaline sucrose gradients. DNA ligation was slower after chemical degradation of DNA by bleomycin than after gamma irradiation. DNA breaks increased approximately linearly with drug concentrations, and were approximately equivalent for ligase-proficient and ligase-deficient cells. These results were unexpected because ligase-deficient, but not ligase-proficient, cells lacked the capacity to eliminate DNA breaks produced by bleomycin. The results indicated that DNA repair did not occur during the chemical degradation of DNA under the experimental conditions. Bleomycin B2 produced considerably more DNA breaks than bleomycin A2 over a range of concentrations in ligase-proficient cells, which tolerated higher numbers of DNA breaks in general than ligase-deficient cells. The chemical analogues are structurally identical except for their cationic C-terminal amine. The actual number of DNA breaks produced by bleomycin A2 or bleomycin B2, and not the concentration of bleomycin A2 or bleomycin B2 per se, determined the amount of cell killing. DNA repair is critical in quantitating DNA breaks produced by chemicals, but was ruled out as a factor in the higher DNA breakage by bleomycin B2 than bleomycin A2.

Bleomycin↗

PubMed1995

DNA repair in humans.

DNA repair is an important molecular defense system against agents that cause cancer, degenerative diseases, and aging. Several repair systems in humans protect the genome by repairing modified bases, DNA adducts, crosslinks, and double strand breaks. These repair systems, base excision, nucleotide excision, and recombination, are intimately connected to transcription and to cell cycle checkpoints. In addition, genotoxic stress induces a set of cellular reactions mediated by the p53 tumor suppressor and the Ras oncogene. These genotoxic response reactions may help the cell survive or enter apoptosis. Damage-response reactions may be utilized as targets of anticancer chemotherapy.

Animals↗