This review article focuses on the molecular aspects of DNA cleavage by synthetic chemical nucleases (transition metal complexes endowed with redox properties and DNA affinity) and natural drugs (cytotoxic agents such as bleomycins or enediynes) . Unlike deoxyribonucleases, which catalyze the nucleophilic attack of water on the phosphorus atom of a particular phosphodiester entity, these nonhydrolytic DNA-cleavers are able to oxidize the sugar units, generally by hydrogen atom abstraction. Examples of oxidative attack on each of the five different C-H bonds of deoxyribose are known, depending on the nature, structure, type of activation, or mode of DNA interaction of the DNA-cleaver. Further evolution at the site of the initial lesion leads to the release of bases, oxidized deoxyribose units, or oxidized sugar fragments appended to the base or the terminal phosphate. In most cases the loss of a part (at least) of a nucleoside, with the concomitant loss of one base information, primarily induces the cleavage of the DNA strand. For both types of DNA cleavage reagents studied within the two last decades, the modes of activation and DNA binding are presented, as well as the details on the mechanism of deoxyribose oxidative degration. Because of the need for highly efficient and highly specific reagents, the development of new artificial and selective D N A cleavers, supported by an improved knowledge of these different mechanisms of DNA cleavage, is to-day a challenging area in the rational design of antitumoral or antiviral agents. as well as in the field of molecular biology.
Reported studies indicate that the association of potassium monopersulfate with [Mn(TMPyP)](OAc)5, a water-soluble manganese porphyrin complex, leads to an efficient reagent for the oxidative cleavage of DNA. Single-strand breaks (SSBs) are observed on double-stranded DNA at manganese porphyrin concentrations as low as 0.5 nM with a short incubation time of 1 min. The number of SSBs linearly varies with the concentration of the manganese complex, and potassium monopersulfate is at least 3 orders of magnitude more efficient as oxygen source than hydrogen peroxide. Cleavage efficiency is optimal in the pH range 7.5-9.0 for a NaCl concentration between 80 and 150 mM or for a MgCl2 concentration of 10 mM. At very low manganese porphyrin concentration and by increasing the incubation time a catalytic cleavage activity of the complex is evidenced: up to 5 SSBs per manganese porphyrin are observed. The high cleavage activity of the monopersulfate-manganese porphyrin system makes it a good candidate for DNA-footprinting experiments.
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