DNA strand break

Administration of dipyridamole-AMP to mice 5—25 min after 1 Gy (100 rad) of TBI y-kradiation is also protective, as indicated by plasma thymidine levels and the amount of saline soluble polynucleotides in the thymus (112). Adding dipyridamole-AMP to in vitro kradiated suspensions of thymocytes enhances the rejoining of DNA strand breaks (112). These post-kradiation effects ate presumably mediated by the activation of extraceUulat adenosine receptors. 

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

Bhusate, L.L., Scott, D.L. and Perrett, D. (1992). Increased DNA strand breaks in mononuclear cells, from patients with rheumatoid arthritis. Ann. Rheum. Dis. 53, 8-12. 

Birnboim, H.C. (1988). A superoxide anion induced DNA strand-break metabolic pathway in human leukocytes effect of vanadium. Biochem. Cell. Biol. 66, 374-381. 

In addition to causing DNA strand breaks, tirapazamine damages the heterocyclic base residues of double-stranded DNA.2 " 2 Similar to authentic, radiolytically generated hydroxyl radical, the drug causes approximately four times more base... 

Nitro PAHs have been shown to exhibit a large variety of biological activities. Included in these are the induction of mutations in bacterial (Table I) and eukaryotic cells (9,17,54-57), the neoplastic transformation of cultured mammalian cells (58-59), and the induction of DNA strand breaks (60), DNA repair (61-62), sister chromatid exchanges (63-64), and chromosomal aberrations (65-66). Nitro PAHs have also been demonstrated to bind cellular DNA in bacteria (67-73) and mammalian cells (74-77), to inhibit preferentially the growth of repair-deficient bacteria (78), to have recombinogenic activity in yeast (66,79-80) and to induce tumors in experimental animals (Table II). 

Antioxidant enzymes also protect against free radical-mediated DNA degradation. For example, SOD and catalase as well as PARS inhibitors suppressed alloxan- and streptozotocin-induced islet DNA strand breaks [122], Uric acid inhibited single-strand DNA breaks induced... 

Gorczyca, W., Gong, J., and Darzynkiewicz, Z., Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick... 

Zhuang, Z. X., Shen, Y., Shen, H. M., Ng, V. andOng, C. N. (1996). DNA strand breaks and poly(ADP-ribose) polymerase activation induced by crystalline nickel subsulfide in MRC-5 lung fibroblast cells, Human Exper. Toxicol., 15, 891-897. 

Costa, M., Heck, J. D. and Robison, S. H. (1982). Selective phagocytosis of crystalline metal sulfide particles and DNA strand breaks as a mechanism for the induction of cellular transformation, Cancer Res., 42, 2757-2763. 

Nickel chloride has been reported to induce DNA strand breaks in CHO cells [435] in a concentration, which did not significantly injure normal cellular division, and DNA-protein cross-links, which were concentration- and time-dependent and preferentially occurred in cells in the late S phase of the cell cycle [436], The nickel cross-linked proteins included nonhistone chromatin proteins, nonhistone DNA-binding proteins and a 30 kDa protein that comigrated electrophoretically with histone HI. Moreover, blocking of cell growth in S phase [249] and induction of DNA repair synthesis in CHO cells [437] and reduction in the fidelity of DNA synthesis [438, 439], have been reported. 

ADPRT activity was suppressed rather than stimulated, as would be expected when DNA strand breaks occur. 

Lipid Peroxidation DNA Strand Breaks Protein Damage... 

Chinese hamster ovary cells (DNA strand breaks) Chromosomal aberration No data — Sze et al. 1996... 

Skare JA, Schrotel KR. 1984. Alkaline elution of rat testicular DNA Detection of DNA strand breaks after in vivo treatment with chemical mutagens. Mutat Res 130 283-294. 

Sze C-C, Shi C-Y, Ong C-N. 1996. Cytotoxicity and DNA strand breaks induced by benzene and its metabolites in Chinese Hamster ovary cells. J Appl Toxicol 16 259-264. 

A recent study showed THC to be toxic to hippocampal neurons, while sparing cortical neurons in concentrations likely to be reached in normal human doses (0.5 pM) (Chan et al. 1998). Apoptotic changes were noted in the hippocampus such as shrinkage of neuronal cell bodies and nuclei as well as DNA strand breaks. THC stimulates release of arachidonic acid, and it was hypothesized that this neurotoxic effect is mediated by cyclooxygenase pathways and free radical generation. In support of this, the toxicity is inhibited by nonsteroidal anti-inflammatory drugs, such as aspirin, and antioxidants such as vitamin E. 

Roots, R. and Okada, S., 1975, Estimation of life times and diffusion distances of radicals involved in x-ray-induced DNA strand breaks ofkilling ofmammalian cells, Radiat.Res. 64 306-320. 

Eram, R. J., and Kufe, D., 1982, DNA strand breaks caused by irrhibitors ofDNA synthesis 1-beta-D-arabinofuranosylcytosine and aphidicoUtL Cancer Res. 42 4050-4053. 

Sundheimer DW, White R, Sipes IG, et al. 1981. Nucleic acid alkylation and production of DNA strand breaks by ethylene dibromide in isolated rat hepatocytes. Fed Proc Fed Am Soc Exp Biol 40 688. 

Beato M, Eisfeld K (1997) Transcription factor access to chromatin. Nucleic Acids Res 25 3559-3563 Becker PB (2002) Nucleosome sliding facts and fiction. Embo J 21 4749-4753 Bekker-Jensen S, Lukas C, Kitagawa R, Melander F, Kastan MB, Bartek J, Lukas J (2006) Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. J Cell Biol 173 195-206... 

Lohse J, Dahl O, Neilsen PE (1999) Double duplex invasion by peptide nucleic acid a general principle for sequence-specific targeting of double stranded DNA. Proc Natl Acad Sci USA 96 11804-11808 Lonn U, Lonn S, Nylen U, Windblad G (1990) Bleomycin-induced DNA lesions are dependent on nucleosome repeat length. Biochem Pharmacol 39(1) 101-107 Lopez-Larraza DM, Bianchi NO (1993) DNA response to bleomycin in mammalian cells with variable degrees of chromatin condensation. Environ Mol Mutagen 21(3) 258—264 Lopez-Larraza DM, Padron J, Rond NE, Vidal Rioja LA (2006) Chromatin condensation and differential sensitivity of mammalian and insect cells to DNA strand breaks induced by bleomycin. Mutat Res 16 April [Epub ahead of print]... 

The enzyme catalyzing the addition of ADP-ribose units onto the histones and itself is poly(ADP-ribose) polymerase or synthetase. Poly(ADP-ribose) polymerase is a nuclear, DNA-dependent enzyme that is stimulated by DNA breaks [302]. This property of the enzyme would target its action to sites that have DNA strand breaks (regions of the genome involved in replication, repair, recombination). The enzyme is associated with chromatin areas and perichromatin regions in interphase Chinese hamster ovary cells [312]. Degradation of the ADP-ribose polymer is catalyzed by the nuclear enzyme poly(ADP-ribose) glycohydrolase and ADP-ribosyl protein lyase. 

Realini and Althaus [313] have put forth the hypothesis that poly(ADP-ribosylation) may have a function in histone shuttling. They propose that poly(ADP-ribose) polymerase directed to sites of DNA strand breaks would auto-modify itself generating multiple ADP-ribose polymers. The polymers would lead to the dissociation of the histones from DNA onto the polymers. The DNA would now be free for processing (e.g., by enzymes involved in excision repair). The action of poly(ADP-ribose) glycohydrolase would degrade the... 

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