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

在执行其功能时，组织和单个细胞暴露在特定的机械力下，如压缩、剪切、拉应力或静水压力。来自我们和其他人的最新证据表明，原子核是一个机械传感器，它可以感知自身的变形，对力做出反应，从而触发机械信号。重要的是，核变形也与DNA损伤有关，但对组织和有机体内平衡的确切机制和功能后果尚不清楚。有趣的是，最近研究表明，与培养的哺乳动物细胞相似，活的秀丽线虫对外部机械载荷的反应与核变形相似。因此，与众所周知和保守的DNA修复机制相结合，线虫提供了一个很好的模型来探索体内和生物尺度上基因组机械保护和机械应激诱导的DNA损伤的机制和后果。我们提出了一个细胞机械生物学和线虫遗传学的多学科项目，以解决力诱导DNA损伤的分子机制和生理后果。结合哺乳动物诱导的多能干细胞的尖端测序、成像和机械操作方法，以及在线虫干细胞室的体内研究，我们将破译干细胞基因组对核形状/体积变化的进化保守机制和组织后果，并研究染色质重排和转录/复制变化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.