Pseudo-DNA damage response in senescent cells

• Published in: Cell cycle (Georgetown, Tex.) Vol. 8; no. 24; pp. 4112 - 4118
• Main Authors: Pospelova, Tatyana V., Demidenko, Zoya N., Bukreeva, Elena I., Pospelov, Valery A., Gudkov, Andrei V., Blagosklonny, Mikhail V
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 15-12-2009
• Subjects: Animals; Binding; Biology; Biomarkers - analysis; Biomarkers - metabolism; Bioscience; Calcium; Cancer; Cell; Cell Line, Tumor; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Nucleus - ultrastructure; Cells, Cultured; Cellular Senescence - genetics; Cycle; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21 - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA - genetics; DNA - metabolism; DNA Damage - genetics; Histones - genetics; Histones - metabolism; Histones - ultrastructure; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Landes; Mice; Neoplasm Proteins - drug effects; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Organogenesis; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proteins; Rats; Signal Transduction - genetics; Sirolimus - pharmacology; Stress, Physiological - genetics; TOR Serine-Threonine Kinases
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.8.24.10215

Cellular senescence is currently viewed as a response to DNA damage. In this report, we showed that non-damaging agents such as sodium butyrate-induced p21 and ectopic expression of either p21 or p16 cause cellular senescence without detectable DNA breaks. Nevertheless, senescent cells displayed components of DNA damage response (DDR) such as γH2AX foci and uniform nuclear staining for p-ATM. Importantly, there was no accumulation of 53BP1 in γH2AX foci of senescent cells. Consistently, comet assay failed to detect DNA damage. Rapamycin, an inhibitor of mTOR, which was shown to suppress cellular senescence, decreased γH2AX foci formation. Thus, cellular senescence leads to activation of atypical DDR without detectable DNA damage. Pseudo-DDR may be a marker of general over-activation of senescent cells.