DNA repair synthesis

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

Probst GS, Hill LE. 1985. Tests for the induction of DNA repair synthesis in primary cultures of adult rat hepatocytes. In Ashby J, de Serres FJ, et al., eds. Progress in mutation research. Vol. 5. Evaluation of short-term tests for carcinogens. Amsterdam, The Netherlands. Elsevier Science Publishers, 381-386. 

Fig. 9. (a) H, 15N] HSQC NMR spectra of 15N-labeled 7 and 2 mol equiv of 5 -GMP after lmin and 30 min of irradiation (, 195Pt satellites) (b) time dependent decrease in concentration of 7 and formation of 7rG and 7rG2 (lines drawn merely to connect points) (c) quantification of in vitro DNA repair synthesis using an extract prepared from the repair-proficient HeLa cell line. Cisplatin was taken as 100%. Adapted from Ref. (35). 

Further experiments focused therefore on [RuCl(en)(r 6-tha)]+ (12) and [RuCl(rj6-p-cym)(en)]+ (22), which represent the two different classes, and their conformational distortion of short oligonucleotide duplexes. Chemical probes demonstrated that the induced distortion extended over at least seven base pairs for [RuCl(rj6-p-cym)(en)]+ (22), whereas the distortion was less extensive for [RuCl(en)(rj6-tha)]+ (12). Isothermal titration calorimetry also showed that the thermodynamic destabilization of the duplex was more pronounced for [RuCl(r 6-p-cym)(en)]+ (22) (89). DNA polymerization was markedly more strongly inhibited by the monofunctional Ru(II) adducts than by monofunctional Pt(II) compounds. The lack of recognition of the DNA monofunctional adducts by HMGB1, an interaction that shields cisplatin-DNA adducts from repair, points to a different mechanism of antitumor activity for the ruthenium-arenes. DNA repair activity by a repair-proficient HeLa cell-free extract (CFE) showed a considerably lower level of damage-induced DNA repair synthesis (about six times) for [RuCl(en)(rj6-tha)] + compared to cisplatin. This enhanced persistence of the adduct is consistent with the higher cytotoxicity of this compound (89). 

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. 

Poirier MC, DeCicco BT, Lieberman MW. 1975. Nonspecific inhibition of DNA repair synthesis by tumor promotors in human diploid fibroblasts damage with N-acetoxy-2-acetylaminofluorene. Cancer Res 35 1392-1397. 

Stich, H.F. and San, R.H.C., Reduced DNA repair synthesis in Xeroderma pigmentosum cells exposed to the oncogenic 4-nitroquinoline 1-oxide and 4-hydroxayminoquinoline 1-oxide, Mutat. Res., 13,279,1971. 

The test is used to identify substances that induce DNA repair in liver cells of treated animals. UDS is DNA repair synthesis after excision and removal of a stretch of DNA containing a region of damage induced by a chemical substance. The test is usually based on the incorporation of tritium-labeled thymidine ( H-TdR) into the DNA of liver cells, which have a low frequency of cells in the S-phase of the cell cycle. 

The test is used to detect DNA repair synthesis and for the detection of micronuclei in the cytoplasm of interphase cells. These micronuclei may originate from acentric fragments (chromosome fragments lacking a centromere) or whole chromosomes that are unable to migrate with the rest of the chromosomes during the... 

This assay is normally carried out only if positive effects have been obtained in earlier in vitro tests. The UDS test measures the DNA repair synthesis which occurs after excision and removal of a stretch of DNA containing the region of damage, induced in hepatocytes of animals treated with the test chemicals. UDS is measured by the uptake of radioactively labelled nucleotide, usually tritium-labelled th)unidine, into the DNA of the damaged hepatocytes. Animals, usually male rats, are treated with the test chemical, and... 

Probst GS, Hill LE. 1980. Chemically-induced DNA repair synthesis in primary rat hepatocytes A correlation with bacterial mutagenicity [Abstract]. Ann NY Acad Sci 349 405-406. 

Durkacz, B.W., Irwin, J. Shall, S. (1981) Inhibition of (ADP-ribose) biosynthesis retards DNA repair but does not inhibit DNA repair synthesis. Biochem. Biophys. Res. Commun., 101, 1433-1441... 

Phenol was reported to induce DNA oxidative damage in human promyelocytic HL60 cells and to inhibit repair of radiation-induced chromosomal breaks in human leukocytes (Morimoto et al., 1976). However, it only slightly inhibited DNA repair synthesis and DNA replication synthesis in WI-38 human diploid fibroblasts (Poirier et al., 1975). 

Ishikawa, T., Kodama, K., Ide, F. Takayama, S. (1982) Demonstration of in vivo DNA repair synthesis in mouse skin exposed to various chemical carcinogens. Cancer Res., 42, 5216— 5221... 

Toschi, L and Bravo, R. (1988) Changes m cyclm/proliferatmg cell nuclear antigen distribution during DNA repair synthesis J Cell Biol 107, 1623—1628. 

Probst GS, Hill LE. 1985. Tests for the induction of DNA repair synthesis in primary cultures of adult rat hepatocytes. Prog Mut Res 5 381-386. 

Stich, H.F., R.H.C. San, and Y. Kawazoe. DNA repair synthesis in mammalian cells exposed to a series of oncogenic and non-oncogenic derivatives of 4-nitro-quinoline 1-oxide. Nature 229 416-419, 1971. 

Unscheduled DNA repair synthesis in mammalian somatic cells in culture, with and without metabolic activation... 

Pilliere F, Levy F, Renier A, et al. 1992. Induction of DNA-repair synthesis (UDS) in rat pleural mesothelial cells by urine of subjects exposed to genotoxic agents. Clin Toxicol 30(2) 223-238. 

Unscheduled DNA synthesis test with mammalian liver cells in vitro UDS in vitro DNA repair DNA repair synthesis... 

The UDS test detects DNA repair synthesis after excision of damaged segments. DNA repair synthesis is demonstrated by autoradiographic measurement of tritium-labeled thymidine incorporation. Liver cells are routinely used for the UDS test because cells in S-phase are rare and easily distinguished from cells undergoing DNA repair and because hepatocytes exhibit... 

Short-term tests are receiving favorable consideration in many laboratories. The report of Stoltz al. and other experts in the field conclude that tests involving mutagenicity (point mutations, DNA damage, chromosome changes as shown by Ames, micronucleus, mouse lymphoma. Drosophila tests), DNA repair synthesis and cell transformation offer promise as screens for carcinogens. 

Figure 11 illustrates the wild, disorganized growth of transformed cells and radiogram showing increased DNA repair synthesis. Mutagenesis was mentioned previously. 

Dimethyl ether is inactive in genetic tests including the Salmonella assay (with and without metabolic activation in at least four strains), HPRT reversion in CHO cells, DNA repair/synthesis in rat liver cells, and the sex-linked recessive lethal test in the fruit fly. 

Nickel chloride induced substantial induction of DNA repair synthesis in cultured Syrian hamster embryo and Chinese hamster ovary cells. Nickel chloride was not mutagenic in an Escherichia coli assay. The ability of nickel chloride to induce chromosomal... 

These pyrolysis products were also found in roasted tea and brandy-type alcoholic beverages (Sugimura and Sato, 1983). In addition, as a result of ethanol metabolism, mutagenic acetaldehyde is formed, while in coffee and tea caffeine, an inhibitor of DNA repair synthesis is present and may also contribute to cancer risk. 

Andrae U, Jahnel P, Greim H. 1979. Induction of DNA repair synthesis in human lymphoblastoid cells by metabolically activated chemicals as shortterm test for DNA-damaging compounds [Abstract]. Mutat Res 64 125. 

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