DNA excision repair

Metabolism and genetic toxicity have been reported to differ with the isomer of nitro-toluene. p-Nitrotoluene was not mutagenic in bacterial assays, but it did increase sister chromatid exchange frequencies and chromosomal aberrations in vitro-, in vivo it did not increase the frequency of micronuclei in bone marrow of treated rodents. Similar findings were reported for the ortho isomer, except that it did not induce chromosomal aberrations in vitro. Only the ortho isomer induces DNA excision repair in the in vivo-in vitro hepatocyte unscheduled DNA synthesis assay. Furthermore, ort/jo-nitrotoluene binds to hepatic DNA to a much greater extent than meta- or para-nitrotoluene, and investigators suggest that it may act similarly to the rodent hepatocarcino-gen 2,6-dinitrotoluene. ... 

Cisplatin (dx-Diamminedichloroplatinum) is a divalent water-soluble platinum containing complex. It reacts directly with DNA, resulting in both intra-and inter-strand cross-links. It also causes DNA breaks and it inhibits DNA replication and RNA transcription. A mechanism for the occurrence of resistance appears to be an increased of the levels of DNA-excision repair enzymes. Cisplatin is used in combination therapies with other anticancer drugs in the treatment of testicular and ovarian cancers and it has also shown high activity against cancers of the bladder, head, neck and endometrium. It is administered intravenously by rapid injection or by continuous infusion. It is for more that 90% bound to... 

Wolff, S., Bodycote, J., Thomas, G.H., Cleaver, J.E. (1975). Sister chromatid exchanges in xeroderma pigmentosum cells that are defective in DNA excision repair or post-replication repair. Genetics 81,349-355. 

Aside from the expression of histidine mutations that are easily detected, other properties have been built into the Salmonella strains by mutation to increase their sensitivity. The strains cure defective in DNA excision repair (uvrB). In this case, the increased sensitivity probably is due to the failure to remove some DNA adducts that could lead to mutation. The strains also possess a mutation (rfa) that removes part of the lipopolysaccharide barrier of the bacterial cell wall and thereby makes the cells more permeable to some chemicals. Finally, Salmonella strains TA98 and TA100 contain the R-factor plasmid pkMIOl,277 which increases sensitivity probably by increasing the activity of an error-prone DNA-repair system. 

Sancar A. DNA excision repair. Annu. Review. Biochem. 1996 65 43-81. 

Sancar A (1994) Mechanisms of DNA excision repair. Science 266 1954-6 Yasui A, Eker AP (1999) DNA photolyases. In Nickoloff lA, Hoekstra MF (eds) DNA damage and repair, vol 11 DNA repair in higher eucaryotes. Humana, Totowa, NJ, pp 9-32... 

Purpose. The purpose of the ex vivo unscheduled DNA synthesis (UDS) test on mammalian liver cells is to evaluate the potential of the test substance to induce DNA excision repair in liver cells of treated animals (usually rodents and preferably rats). An increase in UDS activity is indicative of primary DNA damage and subsequent excision repair (Butterworth et al. 1987 Mirsalis and Butterworth 1980 Mirsalis et al. 1982). 

Loss of High-Fidelity DNA Excision-Repair Systems Can Lead to Cancer... 

Work by Maher et al. (51) on the effect of UV irradiation on human fibroblasts has shown that cell survival is lower and mutation rates higher upon UV irradiation in DNA excision-repair-incompetent cells than in normal cells. Normal cells were also observed to survive a usually lethal and mutagenic UV dose upon being held in confluence (nondividing) for a period of time prior to assessment of survival and mutation rate. These results suggest that this recovery was a result of the increased time given DNA repair mechanisms to remove thymine dimers prior to replication. These workers have also demonstrated that the actual number of DNA alkylation sites removed from the DNA of benzo(a)pyrene exposed fibroblasts by repair mechanisms is directly related to cell survival (52). 

DNA ligase I is the key enzyme for joining Okazaki fragments during DNA replication and for completion of DNA excision-repair processes. 

Nucleotide and base excision repairs. Pyrimidine dimers and other photoproducts may be removed by a process collectively called DNA excision repair comprising of nucleotide excision repair (NER) and base excision repair (BER). In the NER pathway, the dimer-containing DNA strand at the seventh and fourth phosphodiesteric bonds is cleaved in an ATP-dependent nucleolysis and the excised nucleotides are replaced by the action of DNA polymerase followed by that of DNA ligase. 

---