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

一些化学预防和细胞抑制药物以及膳食成分[组蛋白去乙酰化酶（HDAC）抑制剂，嘌呤激活剂如白藜芦醇]调节细胞染色质结构。预计这不仅会影响基因表达，还会影响内源性和外源性DNA修饰的产生和修复，从而影响诱变，从而影响癌症风险。该项目旨在(i)更好地了解染色质结构及其重塑对DNA损伤的产生和修复的影响，以及（ii）评估影响染色质结构的药物的有益和不良影响。到目前为止，我们可以证明白藜芦醇和蔗糖引起的染色质浓缩都会导致培养的哺乳动物细胞的修复延迟，并且HDAC抑制剂（trichostatin-A，丙戊酸）降低AS52细胞的自发和诱导突变率。在用白藜芦醇治疗的小鼠中，观察到对氧化DNA损伤的产生和自发突变的减少有明显的保护作用。在项目的下一个阶段，我们将集中精力了解这些影响背后的机制。我们将分析受影响的修复步骤，识别所涉及的信号因子，并与组蛋白H1过量产生的影响进行比较。在小鼠中，我们将(i)分析HDAC抑制剂对内源性DNA损伤水平的影响，（ii）测试肝脏特异性敲除sirtuine-1的效果。

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.