Coordination Funds

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The stability of the genome is constantly challenged by endogenous and exogenous genotoxic attacks. Cells combat these attacks by activating a DNA damage response (DDR) that promotes DNA repair and induces cell cycle arrest, apoptosis, and cellular senescence. While DNA repair mechanisms and the cellular DDR have been intensely investigated over the past decades, the physiological consequences of genome instability have only recently emerged. Indeed, it is now evident that DNA damage has complex consequences on the organism. In humans, DNA lesions not only cause cancer but also disturb homeostatic processes and consequently promote the aging process and the entire spectrum of age-related diseases, which is underlined by the fact that progeroid syndromes are caused by mutations in DNA repair genes. The Research Unit is comprised of a team of leading experts who propose a highly complementary and deeply interwoven research program aimed at gaining new insights into the physiological causes and consequences of genome instability. We will employ a range of experimental models with a particular emphasis on in vivo animal models, specifically the nematode C. elegans and mouse disease models. The Research Unit will investigate the poorly understood physiological roles of G-quadruplex structures and mechanical stress in challenging the integrity of the genome. We will explore the epigenetic and proteostatic regulatory mechanisms of homeostatic responses to DNA damage by investigating the specific and complex roles of histone remodeling and ubiquitin-mediated regulation of DNA damage signaling and repair. In addition, we will address how transcriptional stress, metabolic adaptation, altered epigenetic chromatin structure and nuclear stability as well as telomere dysfunction and activation of telomere maintenance mechanisms affect organismal homeostasis. We will do this both in the simple nematode worm and in murine progeroid, neurodegenerative and chronic kidney disease models. Taken together, the Research Unit ventures into the largely unexplored area of the physiological causes and consequences of genome instability and will thus significantly advance the current understanding of the impact of DNA damage and genotoxic stress on the organism. As such, the consortium paves the way for the future development of the field by generating synergy between an interdisciplinary group of scientists that explore the mechanistic underpinnings and also the clinical implications of homeostatic processes affected by genome instability.