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At least 343 records · Page 19Linked to original sources
PubMed2005

Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA.

The human Rad50/Mre11/Nbs1 complex (hR/M/N) functions as an essential guardian of genome integrity by directing the proper processing of DNA ends, including DNA breaks. This biological function results from its ability to tether broken DNA molecules. hR/M/N's dynamic molecular architecture consists of a globular DNA-binding domain from which two 50-nm-long coiled coils protrude. The coiled coils are flexible and their apices can self-associate. The flexibility of the coiled coils allows their apices to adopt an orientation favourable for interaction. However, this also allows interaction between the tips of two coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. Here we show that the dynamic architecture of hR/M/N is markedly affected by DNA binding. DNA binding by the hR/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favours intercomplex associations needed for DNA tethering. The hR/M/N complex thus is an example of a biological nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nm distant.

Acid Anhydride Hydrolases↗
PubMed2002

Inter-individual variation in urothelial DNA repair gene expression in vitro.

DNA repair efficiency may play a significant role in individual susceptibility to bladder cancer, the third most common cancer in Europe. Bladder cancer arises from the urothelial cell layer which lines the urinary tract. As DNA repair gene expression levels should reflect DNA repair capacity, we investigated the expression of genes from the base excision, nucleotide excision and mismatch repair pathways in normal human urothelial (NHU) cells in vitro. RNA was extracted from six independent NHU cell lines and expression of 26 DNA repair genes was determined by ribonuclease protection assay. The results show that all the genes analysed were detected in NHU cells in vitro with a similar expression pattern in most cell lines. However, there was some variation between cell lines, with one expressing base excision repair genes very strongly, but another having weak expression of mismatch repair genes. These results suggest that DNA repair genes are constitutively expressed by NHU cells and that there is some inter-individual variation. Prospective studies are required to determine whether these differences in gene expression may play a role in susceptibility to bladder cancer.

Cell Line↗
PubMed1996

The REC1 gene of Ustilago maydis, which encodes a 3'-->5' exonuclease, couples DNA repair and completion of DNA synthesis to a mitotic checkpoint.

Mutation in the REC1 gene of Ustilago maydis results in extreme sensitivity to killing by ultraviolet light. The lethality of the rec1-1 mutant was found to be partially suppressed if irradiated cells were held artificially in G2-phase by addition of a microtubule inhibitor. This mutant was also found to be sensitive to killing when DNA synthesis was inhibited by external means through addition of hydroxyurea or by genetic control in a temperature-sensitive mutant strain defective in DNA synthesis. Flow cytometric analysis of exponentially growing cultures indicated that wild-type cells accumulated in G2 after UV irradiation, while rec1-1 cells appeared to exit from G2 and accumulate in G1/S. Analysis of mRNA levels in synchronized cells indicated that the REC1 gene is periodically expressed with the cell cycle and reaches maximal levels at G1/S. The results are interpreted to mean that a G2-M checkpoint is disabled in the rec1-1 mutant. It is proposed that the REC1 gene product functions in a surveillance system operating during S-phase and G2 to find and repair stretches of DNA with compromised integrity and to communicate with the cell cycle apparatus.

Base Sequence↗
PubMed1975

Absence of specificity in inhibition of DNA repair replication by DNA-binding agents, cocarcinogens, and steroids in human cells.

Although many chemicals, including cocarcinogens, DNA-binding agents, and steroids, inhibit repair replication of ultraviolet-induced damage to DNA in human lymphocytes and proliferating cells in culture, none of these chemicals is specific. Our results show that all the chemicals than they inhibit repair replication. There is thus no cocarcinogens are specific inhibitors of DNA repair or that any of the chemicals studied might be useful adjuncts to tumor therapy merely because of specific inhibition of radiation repair mechanisms.

Animals↗
PubMed1982

Inducible DNA repair in Ustilago maydis.

Maximum survival of UV-irradiated U. maydis required a 2-3 h period of post-irradiation RNA and protein synthesis. Split dose experiments showed that this requirement correlated with the development of a radio-resistant cell state induced by UV doses above 200 Jm-2. Once induced, the radio-resistant state precluded the need for further RNA and protein synthesis for proficient repair of DNA damage caused by a second UV dose. Such radio-resistance was retained for up to 15 hours and it is concluded that this phenomenon represents the expression of an inducible DNA repair process, which is under transcriptional control.

Basidiomycota↗
PubMed1988

Effect of varying the exposure and 3H-thymidine labeling period upon the outcome of the primary hepatocyte DNA repair assay.

The results presented in this report demonstrate that an 18-20 hour exposure/3H-thymidine DNA labeling period is superior to a 4 hour incubation interval for general genotoxicity screening studies in the rat primary hepatocyte DNA repair assay. When DNA damaging agents which give rise to bulky-type DNA base adducts such as 2-acetylaminofluorene, aflatoxin B1 and benzidine were evaluated, little or no difference was observed between the 4 hour or an 18-20-hour exposure/labeling period. Similar results were also noted for the DNA ethylating agent diethylnitrosamine. However, when DNA damaging chemicals which produce a broader spectrum of DNA lesions were studied, differences in the amount of DNA repair as determined by autoradiographic analysis did occur. Methyl methanesulfonate and dimethylnitrosamine induced repairable DNA damage that was detected at lower dose levels with the 18-20 hour exposure/labeling period. Similar results were also observed for the DNA cross-linking agents, mitomycin C and nitrogen mustard. Ethyl methanesulfonate produced only a marginal amount of DNA repair in primary hepatocytes up to a dose level of 10(-3) M during the 4 hour incubation period, whereas a substantial amount of DNA repair was detectable at a dose level of 2.5 X 10(-4) M when the 18-20 hour exposure/labeling period was employed. The DNA alkylating agent 4-nitroquinoline-1-oxide, which creates DNA base adducts that are slowly removed from mammalian cell DNA, induced no detectable DNA repair in hepatocytes up to a toxic dose level of 2 X 10(-5) M with the 4 hour exposure period, whereas a marked DNA repair response was observed at 10(-5) M when the 18-20 hour exposure/labeling period was used.

Animals↗
PubMed1997

The influence of cell growth, detoxifying enzymes and DNA repair on hydrogen peroxide-mediated DNA damage (measured using the comet assay) in human cells.

Single-cell gel electrophoresis (the comet assay) is a sensitive method for detecting strand breaks at the level of individual cells. Cells embedded in agarose are lysed, electrophoresed, and fluorescently stained. Breaks in the DNA release its supercoiling and allow DNA to extend toward the anode, resembling a comet. We have used the comet assay to investigate the influence of growth state, xenobiotic detoxifying enzymes, and DNA repair processes on the response of cultured human cells to oxidative damage. HepG2 and Caco-2 cells are differentiated liver and colon cell lines, respectively. HeLa and GM1899A cells are relatively unspecialized epithelial and lymphoblastoid cells. Substrate-dependent cells showed a cyclical fluctuation of glutathione (GSH) with respect to growth. Enzyme activities (glutathione reductase, glutathione peroxidase, and catalase) varied considerably between cell types and changed with cell growth state. Hydrogen peroxide induced more DNA damage in actively dividing cells than in confluent cultures. Sensitivity to oxidative injury did not correlate with detoxifying enzyme activity. Rather, differences in susceptibility between cells could be correlated with differences in DNA repair capacity. This study highlights the need to standardize experimental conditions if the comet assay is to be employed in the study of genotoxicity.

Catalase↗
PubMed1999

Effects of mutations in DNA repair genes on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae.

A cause of aging in Saccharomyces cerevisiae is the accumulation of extrachromosomal ribosomal DNA circles (ERCs). Introduction of an ERC into young mother cells shortens life span and accelerates the onset of age-associated sterility. It is important to understand the process by which ERCs are generated. Here, we demonstrate that homologous recombination is necessary for ERC formation. rad52 mutant cells, defective in DNA repair through homologous recombination, do not accumulate ERCs with age, and mutations in other genes of the RAD52 class have varying effects on ERC formation. rad52 mutation leads to a progressive delocalization of Sir3p from telomeres to other nuclear sites with age and, surprisingly, shortens life span. We speculate that spontaneous DNA damage, perhaps double-strand breaks, causes lethality in mutants of the RAD52 class and may be an initial step of aging in wild-type cells.

Cellular Senescence↗
PubMed2006

Chromatin modifications in DNA repair.

A requirement of nuclear processes that use DNA as a substrate is the manipulation of chromatin in which the DNA is packaged. Chromatin modifications cause alterations of histones and DNA, and result in a permissive chromatin environment for these nuclear processes. Recent advances in the fields of DNA repair and chromatin reveal that both histone modifications and chromatin-remodeling complexes are essential for the repair of DNA lesions, such as DNA double strand breaks (DSBs). In particular, chromatin-modifying complexes, such as the INO80, SWR1, RSC, and SWI/SNF ATP-dependent chromatin-remodeling complexes and the NuA4 and Tip60 histone acetyltransferase complexes are implicated in DNA repair. The activity of these chromatin-modifying complexes influences the efficiency of the DNA repair process, which ultimately affects genome integrity and carcinogenesis. Thus, the process of DNA repair requires the cooperative activities of evolutionarily conserved chromatin-modifying complexes that facilitate the dynamic chromatin alterations needed during repair of DNA damage.

Animals↗
PubMed1988

The DNA-repair enzyme uracil-DNA glycosylase in the human hematopoietic system.

The expression of the DNA base-excision-repair enzyme uracil-DNA glycosylase in the human hematopoietic system followed a tightly regulated pattern: high enzyme activities were recorded in proliferating bone marrow progenitor cells and in peripheral blood T- and B-cells, both groups of cells requiring the integrity of their genetic information for their proper function. The blood quiescent immunocompetent cells retained their DNA-uracil exclusion capacity, even in the oldest age groups. Peripheral blood mature end cells, granulocytes, platelets and red cells had little activity, consistent with the fact that these cells are anuclear or short-lived, so that no template-primer functions of their DNA are required. Uracil-DNA glycosylase expression is high in all types of human leukemia, providing a selective advantage for survival of leukemic cells. Overall results show that a deficiency of this DNA base-excision-repair pathway is not likely to be an etiopathogenetic factor in the formation of non-random or other chromosomal abnormalities or in the leukemogenesis itself.

Anemia, Megaloblastic↗
PubMed1999

Human DNA repair systems: an overview.

DNA repair systems act to maintain genome integrity in the face of replication errors, environmental insults, and the cumulative effects of age. More than 70 human genes directly involved in the five major pathways of DNA repair have been described, including chromosomal location and cDNA sequence. However, a great deal of information as to the precise functions of these genes and their role in human health is still lacking. Hence, we summarize what is known about these genes and their contra part in bacterial, yeast, and rodent systems and discuss their involvement in human disease. While some associations are already well understood, it is clear that additional diseases will be found which are linked to DNA repair defects or deficiencies.

Animals↗
PubMed1984

[Age-related characteristics of poststress DNA repair in the myocardium].

It has been demonstrated that young and adult rats had age-associated differences in stress-induced lesions and in poststressor repair of DNA synthesis in the myocardium. In both age groups, the DNA repair systems perform an identical scope of work aimed at abolition of poststressor lesions with the difference that in young rats, the repair is completed 2 days and in adult rats 3 days after exposure to stress is discontinued.

Aging↗
PubMed2004

Relative contribution of DNA repair, cell cycle checkpoints, and cell death to survival after DNA damage in Drosophila larvae.

BACKGROUND: Components of the DNA damage checkpoint are essential for surviving exposure to DNA damaging agents. Checkpoint activation leads to cell cycle arrest, DNA repair, and apoptosis in eukaryotes. Cell cycle regulation and DNA repair appear essential for unicellular systems to survive DNA damage. The relative importance of these responses and apoptosis for surviving DNA damage in multicellular organisms remains unclear. RESULTS: After exposure to ionizing radiation, wild-type Drosophila larvae regulate the cell cycle and repair DNA; grp (DmChk1) mutants cannot regulate the cell cycle but repair DNA; okra (DmRAD54) mutants regulate the cell cycle but are deficient in repair of double strand breaks (DSB); mei-41 (DmATR) mutants cannot regulate the cell cycle and are deficient in DSB repair. All undergo radiation-induced apoptosis. p53 mutants regulate the cell cycle but fail to undergo apoptosis. Of these, mutants deficient in DNA repair, mei-41 and okra, show progressive degeneration of imaginal discs and die as pupae, while other genotypes survive to adulthood after irradiation. Survival is accompanied by compensatory growth of imaginal discs via increased nutritional uptake and cell proliferation, presumably to replace dead cells. CONCLUSIONS: DNA repair is essential for surviving radiation as expected; surprisingly, cell cycle regulation and p53-dependent cell death are not. We propose that processes resembling regeneration of discs act to maintain tissues and ultimately determine survival after irradiation, thus distinguishing requirements between muticellular and unicellular eukaryotes.

Animals↗
PubMed2001

A novel fluorometric oligonucleotide assay to measure O( 6)-methylguanine DNA methyltransferase, methylpurine DNA glycosylase, 8-oxoguanine DNA glycosylase and abasic endonuclease activities: DNA repair status in human breast carcinoma cells overexpressing methylpurine DNA glycosylase.

DNA repair status plays a major role in mutagenesis, carcinogenesis and resistance to genotoxic agents. Because DNA repair processes involve multiple enzymatic steps, understanding cellular DNA repair status has required several assay procedures. We have developed a novel in vitro assay that allows quantitative measurement of alkylation repair via O(6)-methylguanine DNA methyltransferase (MGMT) and base excision repair (BER) involving methylpurine DNA glycosylase (MPG), human 8-oxoguanine DNA glycosylase (hOGG1) and yeast and human abasic endonuclease (APN1 and APE/ref-1, respectively) from a single cell extract. This approach involves preparation of cell extracts in a common buffer in which all of the DNA repair proteins are active and the use of fluorometrically labeled oligonucleotide substrates containing DNA lesions specific to each repair protein. This method enables methylation and BER capacities to be determined rapidly from a small amount of starting sample. In addition, the stability of the fluorometric oligonucleotides precludes the substrate variability caused by continual radiolabeling. In this report this technique was applied to human breast carcinoma MDA-MB231 cells overexpressing human MPG in order to assess whether up-regulation of the initial step in BER alters the activity of selected other BER (hOGG1 and APE/ref-1) or direct reversal (MGMT) repair activities.

Alkylation↗
PubMedDate not supplied

[Activation of the DNA repair system in tissues of mice subjected to chronic gamma irradiation].

Mice exposed to gamma-quanta during 47 and 82 days at a dose-rate of 1.3 mGy/h and cumulative doses of 1.45 and 2.54 Gy, respectively, were subsequently subjected to a single acute irradiation with a dose of 20 Gy. Repair of DNA damages induced by the acute exposure was shown to proceed in the brain, pulmonary and splenic tissues of chronically exposed mice more readily than in the tissues of mice not subjected to chronic irradiation. The data obtained indicate that the induced adaptive response activates DNA repair in tissues of mice exposed to long-term low-level radiation.

Animals↗