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

在执行它们的功能时，组织和单个细胞暴露于特定的机械力，如压缩、剪切、拉伸应力或静水压力。最近来自我们和其他人的证据表明，细胞核是一种机械传感器，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，但精确的机制和对组织和有机体稳态的功能后果尚不清楚。有趣的是，最近有研究表明，活的秀丽隐杆线虫对外部机械负荷的反应与培养的哺乳动物细胞相似，具有核变形。因此，连同已被充分理解和保守的DNA修复机制，秀丽隐杆线虫为探索基因组机械保护和机械应力诱导的DNA损伤的机制和后果提供了一个很好的模型。我们提出一个细胞力学生物学和秀丽隐杆线虫遗传学的多学科项目，以解决力诱导的DNA损伤的分子机制和生理后果。结合尖端的哺乳动物诱导多能干细胞的测序、成像和机械操作方法，以及在秀丽隐杆线虫干细胞室（种系）的体内研究，我们将破译干细胞基因组对核形状/体积变化的反应的进化保守机制和有机体后果，并研究染色质重排和转录/复制改变如何影响基因组完整性。

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.