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

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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.