Influence of modulators of chromatin structure and dynamics on the generation and repair of oxidative DNA damage

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Several chemopreventive and cytostatic drugs as well as dietary constituents [histone deacetylase (HDAC) inhibitors, sirtuine activators such as resveratrol] modulate the cellular chromatin structure. This is expected to influence not only gene expression, but also the generation and repair of endogenous and exogenous DNA modifications and thus affect mutagenesis and, in consequence, the cancer risk. This project is aimed at (i) a better understanding of the impact of the chromatin structure and its remodelling on the generation and repair of DNA damage and (ii) at the assessment of beneficial and adverse effects of drugs that affect chromatin structure. So far, we could show that both resveratrol and chromatin condensation by sucrose cause a retardation of repair in cultured mammalian cells and that HDAC inhibitors (trichostatin-A, valproate) decrease the spontaneous and induced mutation rates in AS52 cells. In mice treated with resveratrol, a pronounced protection against the generation of oxidative DNA damage and a reduction of spontaneous mutations was observed. In the next period of the project, we will concentrate on the understanding of the mechanisms underlying these effects. We will analyse the steps of repair that are affected, identify signalling factors involved and compare with the effects of a histone H1 overproduction. In mice, we will (i) analyse the influence of HDAC inhibitors on endogenous DNA damage levels and (ii) test the effects of a liver-specific knock-out of sirtuine-1.