Repair of DNA Lesions

Because of the complex interactions described above, it is important to determine the number of lesions present in the test system at zero time. Although this is not operationally possible in all systems, one could measure the amount of alkylation at zero time (Roberts et al., 1971), or in the case of damage induced by ultraviolet (UV) radiation one can ascertain the percentage of thymidine in cyclobutane pyrimidine dimers (Carrier and Setlow, 1971). With most chemical DNA-damaging agents, however, the nature of the primary lesion is obscure. 

---

This work provides important evidence for elucidating the cytotoxic effect of the ruthenium-arene complexes and the influence of the arene thereon, for instance with respect to excision repair of DNA lesions and DNA destabilization. It also established two different classes of Ru(II) arene anticancer drugs, i.e. those bearing an arene that has the possibility to intercalate and those that do not. This distinction is important as we will see further differences in DNA binding interactions for these two classes (vide infra). 

Ristau C, Bolt HM, Vangala RR Formation and repair of DNA lesions in kidneys of male mice after acute exposure to methyl chloride. Arch Toxicol 6Y254-256, 1990... 

The more delayed and prolonged mechanisms by which the checkpoint silences CDKl activity is through the activation of the p53 pathway. Activation of p53 is achieved by phosphorylation by ATM/ATR or Chkl/Chk2 and results in nuclear localization, tetramerization, and stimulation of p53 transcriptional activity toward p21. In G2, BRCAl can stimulate p21 expression in a p53 independent fashion (193) along with two other p53 targets, GADD45 and 14-3-3e, BRCAl may cooperate to achieve maximal inhibition of CDKl and to prevent mitotic entry to allow for repair of DNA lesions (68). 

Repair of DNA lesions and unscheduled DNA synthesis in response to DNA primary damage. 

Purpose. The purpose of the sister chromatid exchange (SCE) assay is to evaluate the potential of the test substance to induce repair of DNA lesions by homologous recombination in cells of treated animals (potentially all species, usually rodents) (Latt et al. 1981 Helleday 2003). It can easily be applied to any dividing tissue, such as bone marrow and peripheral blood, from which cell suspensions can be isolated and analyzed. 

Thus evidence for this mechanism comes from studies of the interaction of the drugs with nucleic acids and nucleic acid components, from observations on the effects of the drugs on DNA synthesis, and from observations relating to repair of DNA lesions and cytotoxicity. First we will consider the reactions of the drug with nucleic acids. 

As Fig. 18 shows, the former two compounds, which were formed by the reaction of MTBI with Leu and Phe, were able to inhibit the IQ mutagenicity at concentrations of 125-500 fxg/ml when incubated simultaneously with IQ in the presence of S9, and the compound derived from MTBI and Met showed an antimutagenic activity at a dose of 500 Hg/ml by simultaneous treatment with IQ. However, no inhibition of the IQ mutagenicity was observed when the test compounds were incubated with the bacteria that had been preincubated with IQ to induce mutation. This suggests that these 2-thiohydantoins are not involved in the repair of DNA lesions, but they are involved with the inactivation of IQ or the inhibition of S9-mediated metabolic activation of the mutagen. 

Repair of DNA lesions is achieved through different rep>air mechanisms, i.e. base excision repair (BER), nucleotide excision repair (NEK), mismatch repair (MMR) and double strand break repair (DSBR) or the combinations of different repair mechanisms dependent on the... 

The comutagenicity of arsenite and its lack of DNA-damaging ability suggests that it may modify the repair of DNA lesions induced by other agents. This theory is supported by the finding that arsenic trioxide inhibits... 

Braithwaite E, Wu X, Wang Z Repair of DNA lesions meehanisms and relative repair... 

---