CRA4 Genotoxic Stress

Coordinator: Zhao-Qi Wang

Every cell is equipped with the DNA damage response (DDR), which involves damage-induced signalling resulting in a network of cellular responses, consisting of DNA repair, cell cycle checkpoint and apoptosis as well as transcription activation. The genome within the cell is constantly being challenged by DNA-damaging agents. Accumulating evidence shows that DDR changes metabolism in response to stress stimuli, such as DNA damage, inflammatory cytokines and environmental stressors. The DDR is primarily governed mainly by two protein kinases ATM and ATR, which are activated by DNA double strand breaks and single strand breaks or stalled replication forks, respectively. Together with PI3K and PI3K-related kinases, they control the balance of destructive (cell death) and regenerative (vitality) processes in response to various stress stimuli, depending on the dose, origin and dynamics. In CRA4, we propose to study the strength- and temporal-spatial-dependent effects of noxious cues that ultimately induce DDR. As described in the chapters below, our focus will lay on the differential signalling reactions of PARP1 (an early DDR molecule), PI3K-, mTOR-dependent pathways in the stress reactions elicited by direct DNA damage and inflammatory processes, for example in sepsis. The early signalling induced by inflammatory factors (e.g. cytokines), stress signalling pathway mediated by PI3K, or by direct DNA damage, all will trigger a net reaction of downstream cascades including activation of PARP1 (an early DDR molecule), the PI3K- and mTOR pathways, transcription action of target genes, in the course of the inflammation response. The interactive function of these pathways dictates the cell fate and ultimately the tissue maintenance and functionality. Thus, studying the network of these fundamental cellular processes will improve our understanding of tissue homeostasis and, if failed, pathologies such as cancer, septic shock and organ impairment.