BN seminar - Tyler Kirby (Cornell, USA): “Lamin mutations cause mechanically-induced nuclear envelope rupture and DNA damage in muscle fibers”



13:00 hrs


A1.100, building 58, Delft


Mutations in the nuclear envelope proteins lamin A and C cause a variety of diseases, collectively referred to as laminopathies. These diseases, which include Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, and dilated cardiomyopathy, predominantly affect striated muscle. The molecular mechanism for how mutations in these nearly ubiquitously expressed proteins cause striated muscle-specific phenotypes remains unclear. One hypothesis postulates that lamin mutations impair the mechanical stability of the nucleus, rendering nuclei more fragile and more susceptible to force-induced damage in mechanically active tissues; however, direct evidence for this hypothesis has been lacking. Using novel microfluidics-based assays and in vitro differentiation assays, combined with live-cell fluorescent reporters, I directly tested this hypothesis in primary muscle cells isolated from lamin A/C-mutant mice. My talk will focus on my most recent findings, which show that mutations in lamin A/C render the nucleus susceptible to mechanically-induced damage, resulting in the transient loss of nuclear envelope integrity. This loss of nucleocytoplasmic compartmentalization, termed nuclear envelope rupture, results in widespread DNA damage and activation of DNA-damage response pathways. I found that these nuclear ruptures are the result of forces generated during nuclear migration within the myofiber. In addition, I observed these nuclear defects in mouse models of laminopathies, providing evidence that these events may contribute to the disease pathogenesis in vivo. Finally, I will present my recent findings where I used transcriptomics to identify molecular pathways that could underlie the cellular dysfunction that accompanies these nuclear defects, in an effort to identify potential novel therapeutic targets. In showing that lamin A/C mutations impair mechanical stability of the nucleus, leading to DNA damage, I provide new insights to explain why these mutations might present in a tissue-specific phenotype.