Mechanical-stress induced DNA damage and genome mechanoprotection in cellular and organismal homeostasis

细胞和有机体稳态中机械应力诱导的 DNA 损伤和基因组机械保护

• 批准号: 515756021
• 负责人: Professor Dr. Björn Schumacher
• 金额: --
• 依托单位: Institute for Genome Stability in Ageing and Disease
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515756021?language=en
• 关键词: Mechanical; stress; induced; DNA; damage

While executing their functions, tissues and single cells are exposed to specific mechanical forces such as compression, shear, tensile stress, or hydrostatic pressure. Recent evidence from us and others points to the nucleus as a mechanosensor that senses its own deformation in response to force to trigger mechanosignaling. Importantly, nuclear deformation is also associated with DNA damage, but the precise mechanisms and functional consequences to tissue and organismal homeostasis remain unclear. Intriguingly, it was recently demonstrated that living Caenorhabditis elegans nematodes respond to extrinsic mechanical loading with nuclear deformation similar to cultured mammalian cells. Thus, together with the well-understood and conserved DNA repair mechanisms, C. elegans provides an excellent model to probe mechanisms and consequences of genome mechanoprotection and mechanical stress-induced DNA damage in vivo and on the organismal scale. We propose a multidisciplinary project of cell mechanobiology and C. elegans genetics to tackle the molecular mechanisms and physiological consequences of force-induced DNA damage. Combining cutting edge sequencing, imaging, and mechanical manipulation approaches in mammalian induced pluripotent stem cells with in vivo studies in the C. elegans stem cell compartment, the germline, we will decipher evolutionarily conserved mechanisms and organismal consequences of stem cell genome responses to nuclear shape/volume changes and study how chromatin rearrangements and transcriptional/replication alterations impact genome integrity.

在执行其功能时，组织和单细胞暴露于特定的机械力，例如压缩、剪切、拉伸应力或静水压力。我们和其他人最近的证据指出，细胞核是一个机械传感器，它可以感知自身的变形，以响应力，从而触发机械信号。重要的是，核变形也与DNA损伤有关，但对组织和生物体内平衡的确切机制和功能后果仍不清楚。有趣的是，它最近被证明，生活秀丽隐杆线虫响应外部机械负荷与核变形类似培养的哺乳动物细胞。因此，连同已被充分理解和保守的DNA修复机制，C。elegans提供了一个很好的模型，以探测机制和基因组mechanoprotection和机械应力诱导的DNA损伤在体内和生物体规模的后果。我们提出了一个多学科的细胞机械生物学和C。elegans遗传学来解决力诱导DNA损伤的分子机制和生理后果。将哺乳动物诱导多能干细胞的尖端测序、成像和机械操作方法与C。线虫干细胞隔室，种系，我们将破译进化保守的机制和干细胞基因组对核形状/体积变化的反应的有机后果，并研究染色质重排和转录/复制改变如何影响基因组的完整性。