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DNA a target for oxidative stress

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During oxidative stress the excess of uncontrolled oxygen reactive species attack all the important macromolecules of the cell. Even if damages to lipids and proteins are harmful for the cell, the attack of DNA can be more disastrous. DNA is a particular molecule that store all the memory of 500 000 sort of our proteins and that cannot be destroyed and replace. Paradoxically the bases of DNA are very sensitive to oxidation and particularly the guanine. Oxidative stress can so lead to a great number of direct oxidative derivative of bases, many described by our lab: 8-oxo guanine, 8-nitro guanine, formamidopyrimidine, 8-oxo adenine, formimido uracile, 5-hydroxy cytosine, 5-hydroxy methyl uracile, thymine diol, oxazolone … But other chemical disorders can occur by attack of the bond between base and deoxyribose creating an abasic site or by attack of deoxyribose itself creating a strand break. Indirect damages can occur and be very difficult to repair by a chemical reaction between the product of lipid peroxidation or nuclear protein oxidation creating adducts such as MDA-guanine, MDA-lysine, 5-Hydroperoxymethyl-2′deoxyuridine … The role of the various metals linked in the nucleus to DNA (Fe, Mg, Zn, Cu, Ni, Cd…) is crucial to amplify damages for some or protect for the others.

Each day our cells are subject to many attack of DNA and it is approximate that 104 oxidative bases are formed each day in each cell. Fortunately the integrity and fidelity of human genome can be maintained by a great variety of DNA repair systems.

The more important are base-excision repair and nucleotide-excision repair that can be coupled to transcription or to cell cycle. Sophisticated mechanism rely these repair systems to replication or apoptosis by the assembly of large protein complexes resulting in a check point for the cell to dye or survive.

DNA damages can be measured in tissue or blood by a very sensitive but less specific technique that is the comet assay or by a more specific one the liquid chromatography-tandem mass spectrometry. We have developed these techniques that permit us to establish specific pattern of damages according to the nature of a particular oxidative species. We are able to demonstrate the effect of factors such as nutrition or aging in animal models or in human. We also built up sensitive methods to evaluate the mutagenic capacity of a chemically defined damage, by using fluorescence transfer or original DNA micro array.

Unfortunately this repair system can become inefficient when they are genetically miscoded, nutritionally deficient in a cofactor (such as reduced thioredoxine, zinc) or overwhelmed by a strong oxidative stress. In such case some damage will be misinterpreted by infidel translesional DNA polymerase and creates a mutation in this genetic position, some other damages cannot be overpassed by polymerase and lead to apoptosis.

The biological consequences of DNA damages are so very important as they are a source of mutagenesis that is a beneficial for species evolution but also unfortunately the first step for carcinogenesis. In this last case apoptosis is the last defense to prevent the tissue from cancer. So the use of large amount of antioxidant, that can suppress DNA damage but also apoptosis, can be as beneficial as deleterious according to the dose and time of.
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Document Type: Abstract

Affiliations: Laboratoire ‘Lésions des Acides Nucléiques’, CNRS-CEA-Université de Grenoble, France

Publication date: April 1, 2004

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