Research Papers: Gerotarget (Focus on Aging):
Senoptosis: non-lethal DNA cleavage as a route to deep senescence
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Maja Studencka1 and Jörg Schaber1
1 Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany
Jörg Schaber, email:
Keywords: apoptosis, DNA damage, EndoG, SASP, senescence, Gerotarget
Received: September 27, 2016 Accepted: February 06, 2017 Published: February 25, 2017
DNA-damage-induced apoptosis and cellular senescence are perceived as two distinct cell fates. We found that after ionizing radiation (IR)-induced DNA damage the majority (up to 70 %) of senescent human diploid fibroblasts (HDFs) were subjected to controlled cleavage of DNA, resulting in the establishment of a viable and stable sub-G1 population, i.e. deeply senescent cells. We show that in senescent HDFs this DNA cleavage is triggered by modest loss of the mitochondrial membrane potential, which is not sufficient to activate caspases, but strong enough to release mitochondrial endonuclease G (EndoG). We demonstrate that upon γ-irradiation in HDFs EndoG translocates into the nucleus playing an essential role in the non-lethal cleavage of damaged DNA. Notably, the established sub-G1 cell population does not contribute to the senescence-associated secretory phenotype (SASP), however, it exhibits increased senescence-associated β-galactosidase activity. We show that EndoG knockdown causes an increase in DNA damage, indicating a role of this enzyme in DNA repair. Thus, we conclude that IR-induced deep senescence of HDFs exhibits features of both senescence, such as cell cycle arrest and viability, and apoptosis like reduced DNA content and no SASP, and, resembles uncomplete or stalled apoptosis, a phenomenon we term senoptosis.
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