Senoptosis: non-lethal DNA cleavage as a route to deep senescence

Abstract

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? -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.

Endonuclease G promotes mitochondrial genome cleavage and replication

“…Ultimately the linearised damaged mtDNA molecules are most likely degraded, as mitochondria lack efficient DSB repair mechanisms [ 60 ]. In the nucleus EndoG-mediated cleavage activates DSB repair mechanisms instead of DNA degradation [ 20 , 61 , 75 ].…”

The Effect of Brazilin from Caesalpinia sappan on Cell Cycle and Modulation and Cell Senescence in T47D cells

“…Based on the cell cycle analysis we observed that brazilin caused cell accumulation on subG1 and G2/M phase ( Figure 2B,C). The sub G1 phase population is often related to apoptotic cells, as one of the apoptotic characteristics is DNA fragmentation, which results in a reduced content of DNA (Studencka and Schaber, 2017). This result was suggesting that the cells were directed into apoptosis via G2/M arrest.…”

Regulation of the mitochondrial permeability transition pore and its effects on aging

“…However, it was also found that mitochondrial fission proteins are increased during CR, and an explanation could be related to the role of fission in mitochondrial biogenesis and CR [ 123 ]. Depolarized mitochondria were also found in senescent cells [ 124 – 126 ], where autophagy is known to take place [ 127 , 128 ]. In fact, autophagy was found to be activated in senescence although the details of the interplay between autophagy, senescence and apoptosis have to be clarified [ 128 , 129 ].…”