Surprisingly, activation of these DDR kinases is independent of canonical pathway triggers, such as DNA damage or replication stress. Instead, structural deformation of the NL appears to be a component of checkpoint activation. Despite remarkably normal oogenesis in d-emerin/otefin, chk2 double mutant ovaries, the rescued oocytes do not support embryogenesis, indicating these oocytes are defective. Such findings suggest that the NL checkpoint contributes to maintenance of gamete quality. Our current studies are focused on defining the molecular features of this checkpoint.

Our studies have a broad impact on understanding mechanisms responsible for loss of stem cells during physiological aging and age-dependent diseases. These states commonly are accompanied by changes in nuclear morphology that are associated with persistent DNA damage signaling. Thus, our studies have the potential to advance therapeutics that delay or eliminate pathologies that lead to stem cell loss.