DNA damage response and DNA repair triggered by genotoxic phenylpropanoids in the diet

点击翻译按钮获取中文摘要

Phenylpropanoids or Phenylpropenes (PP) are naturally occurring ingredients of herbs and spices such as basil, nutmeg, anise and calamus. They are chemical derivatives of benzol with an unsaturated C3-side chain, which contains either a terminal double bond (allylic PP) or an internal double bond (1-propenylic PP). These compounds undergo metabolic activation in a structure-dependent manner: 1-propenylic PP via Cytochrome P450 enzymes (CPY) and allylic PP via CYP and Sulfotransferases (SULT). The major target organ represents the liver, where PP are known to act genotoxic and carcinogenic. However, it is largely unknown how the DNA damage response confers protection against PP-induced DNA adducts and which DNA repair pathways are involved in DNA adduct removal. Furthermore, it is unclear how defects in DNA repair will affect cell survival and genome integrity.The objective of this study is to understand the DNA damage response triggered by PP-DNA adducts and to reveal the engaged DNA repair mechanism. To this end, the allylic PP Methyleugenol and the 1-propenylic PP ß-Asaron will be studied, which are both relevant in food. Metabolic competent liver cell lines as well as primary liver cells with specific defects in DNA repair will be used. Due to the results obtained in our preliminary studies, we will focus on global-genomic and transcription-coupled nucleotide excision repair (GG-NER and TC-NER, respectively). The followings issues should be addressed with these models: 1.) Which type of DNA damage response in triggered in cells upon DNA adduct formation by allylic and 1-propenylic PP and how is this regulated, 2.) What is the relevance of GG-NER and TC-NER for the removal of PP-induced DNA adducts and are there differences concerning dG-N2- and dA-N6-adducts, and 3.) What are the biological consequences of PP-induced DNA damage with regard to cytotoxicity and clastogenicity, and how are these endpoints influenced by defects in GG-NER and TC-NER, respectively.