Coordination Funds

基因组的稳定性不断受到内源性和外源性基因毒性攻击的挑战。细胞通过激活DNA损伤反应（DDR）来对抗这些攻击，DDR促进DNA修复，诱导细胞周期阻滞、细胞凋亡和细胞衰老。虽然DNA修复机制和细胞DDR在过去几十年中已经得到了广泛的研究，但基因组不稳定的生理后果直到最近才出现。事实上，现在很明显，DNA损伤对生物体有复杂的影响。在人类中，DNA损伤不仅会导致癌症，还会扰乱体内平衡过程，从而促进衰老过程和所有与年龄相关的疾病，这一事实强调了类早衰综合征是由DNA修复基因突变引起的。研究单位由一组领先的专家组成，他们提出了一个高度互补和深度交织的研究计划，旨在获得关于基因组不稳定性的生理原因和后果的新见解。我们将采用一系列实验模型，特别强调体内动物模型，特别是线虫秀丽隐杆线虫和小鼠疾病模型。该研究单位将调查尚不清楚的g -四重体结构和机械应力在挑战基因组完整性中的生理作用。我们将通过研究组蛋白重塑和泛素介导的DNA损伤信号传导和修复调节的具体和复杂作用，探索DNA损伤稳态反应的表观遗传和蛋白稳态调节机制。此外，我们将讨论转录应激、代谢适应、表观遗传染色质结构和核稳定性的改变以及端粒功能障碍和端粒维持机制的激活如何影响生物体的稳态。我们将在简单线虫和小鼠类早衰症、神经退行性疾病和慢性肾脏疾病模型中这样做。总而言之，研究单位冒险进入基因组不稳定的生理原因和后果的大部分未开发领域，因此将大大促进目前对DNA损伤和基因毒性应激对生物体的影响的理解。因此，该联盟通过在一个跨学科的科学家小组之间产生协同作用，为该领域的未来发展铺平了道路，这些科学家小组探索了受基因组不稳定性影响的体内平衡过程的机制基础和临床意义。

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.