Galanopoulou, O.; Tachmatzidi, E. C.; Deligianni, E.; Botskaris, D.; Nikolaou, K. C.; Garganis, S.; Dalezios, Y.; Chalepakis, G.; Talianidis, I.

Cellular senescence is driven by diverse effector programs, leading to irreversible growth arrest, DNA damage and complex secretomes. Here we show that, in liver-specific Setd8-KO mice, after mitogen treatment, a significant number of hepatocytes become senescent and display unusual features such as enlarged nuclei, chromosomal hyperploidy and nuclear engulfments progressing to the formation of intranuclear vesicles. These vesicles contain glycogen, cytoplasmic proteins and even entire organelles. We term this process endonucleosis. Experiments with Setd8/Atg5 double knockout mice, demonstrated that endonucleosis requires the function of the autophagy machinery. Endonucleosis and hyperploidization are temporary, early features of senescence. Larger vesicles brake down into microvesicles over time and are eventually eliminated. The results reveal a senescence phenotype, which function as part of survival mechanisms to prevent necrotic death.