Genetic and Molecular Analysis of DNA Damage induced Apoptosis and Cell Cycle Arrest in C. elegans

点击翻译按钮获取中文摘要

We still know relatively little about the molecular connection between the sensing of DNA damage and the activation of the programmed cell death machinery and therefore use the C. elegans germ line as model system to study ionic radiation induced cell death and cell cycle arrest. As proposed in Ga 703/1-1 we cloned and genetically characterized the C. elegans rad-5 checkpoint gene that turned out to be evolutionarily conserved2. Furthermore, as part of a collaborative effort using functional-genomics and RNAi-based approaches we could show that conserved genes, which were previously implied in yeast checkpoint signaling, also function in C. elegans DNA damage response pathways3. Furthermore, we performed a forward genetics screen, through which we found novel candidate mutations involved in DNA damage induced apoptosis, (A. Gartner, unpublished). Finally, we could define a functional worm homolog of the mammalian p53 tumor suppressor4 . As part of this proposal (extension of the project Ga 703/1-1) we aim at further characterizing the novel rad-5-checkpoint gene (task-1). In addition, we plan to positionally clone the checkpoint gene corresponding to the gt11 mutation, which we have identified in a pilot genetic screen (task-2). By continuing with our genetic screen, we aim at defining new DNA damage checkpoint mutations and we want to start to positionally clone the corresponding genes (task-3). Finally we plan to start to put novel and already known damage response genes into genetic and biochemical pathways (task-4) using biochemical genetic and cytological methods. In summary we believe to contribute to a deeper understanding of DNA damage response.