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

Area of Science:

• Cell Biology
• Genetics
• Biochemistry

Background:

• DNA damage triggers apoptosis and cellular senescence as distinct cell fates.
• Senescent cells typically arrest cell cycle and exhibit senescence-associated secretory phenotype (SASP).

Purpose of the Study:

• Investigate the fate of senescent human diploid fibroblasts (HDFs) after ionizing radiation (IR)-induced DNA damage.
• Characterize the mechanism and features of IR-induced deep senescence in HDFs.

Main Methods:

• Induction of senescence and DNA damage in HDFs using ionizing radiation (IR).
• Analysis of DNA cleavage, mitochondrial membrane potential, and caspase activation.
• Assessment of endonuclease G (EndoG) translocation and its role in DNA cleavage and repair.
• Evaluation of senescence-associated β-galactosidase activity and SASP.

Main Results:

• Up to 70% of senescent HDFs underwent controlled DNA cleavage, forming a viable sub-G1 population (deeply senescent cells).
• Mitochondrial membrane potential loss triggered EndoG release, causing nuclear translocation and non-lethal DNA cleavage in senescent HDFs.
• Deeply senescent cells showed increased senescence-associated β-galactosidase activity but lacked SASP, resembling incomplete apoptosis.

Conclusions:

• IR-induced deep senescence in HDFs exhibits characteristics of both senescence (cell cycle arrest, viability) and apoptosis (reduced DNA content, no SASP).
• This phenomenon, termed senoptosis, represents a stalled or incomplete apoptotic process.
• Endonuclease G plays a crucial role in IR-induced DNA cleavage and potentially in DNA repair during senoptosis.