Induction of Futile DNA Repair Processes by Bifunctional Intercalators
Ditercalinium is a DNA bifunctional intercalator endowed with antitumor properties. It binds to DNA with high affinity, forming a noncovalent and reversible complex. NMR studies of a ditercalinium oligonucleotide complex have revealed that, in the DNA complex, the linking chain of ditercalinium is located in the large groove of the DNA double helix, and that a bending of the double helix is induced toward the small groove.
It was found that ditercalinium and its antitumor analogues, but not its monomeric derivative, elicit a specific toxicity on polA strains of E. coli. This toxicity is suppressed by the uvrA mutation. In polA strains, ditercalinium induces SOS functions, although no immediate DNA synthesis arrest is observed. In the thermosensitive ligase deficient strain lig7, single-strand breaks accumulate at non-permissive temperature. It is proposed that the structural alteration induced in DNA after ditercalinium binding is recognized by the UVR repair process in E. coli. Because of the noncovalent nature of the DNA-ditercalinium complex, this structural alteration acts as a mock lesion or a lure which triggers a futile and abortive repair process.
In mammalian cells, ditercalinium causes a delayed cytotoxicity. Cells treated with ditercalinium die only 5 to 6 generations after drug exposure. Mitochondrial DNA is rapidly lost, and no damage is observed on nuclear DNA. It is hypothesized that the loss of mitochondrial DNA is related to a malfunctioning of a DNA repair process. DNA structural alterations, caused by agents forming non-covalent and reversible complexes with DNA, appear as a new type of lesion which could, in some conditions, completely fool the DNA repair machinery, and which would then become deleterious for the cells.
KeywordsNonpermissive Temperature Covalent Adduct polA Strain Reversible Complex Small Groove
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