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Updated: May 25, 2026

Techniques to Induce and Quantify Cellular Senescence
06:51

Techniques to Induce and Quantify Cellular Senescence

Published on: May 1, 2017

Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress

Kamini Singh1, Shigemi Matsuyama, Judith A Drazba

  • 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Autophagy
|January 14, 2012
PubMed

Insights

A Cyclin E fragment (p18-CycE) drives autophagy and senescence following DNA damage. Autophagy inhibition promotes apoptosis by stabilizing p18-CycE, revealing new cell survival pathways.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Autophagy is crucial for cell survival and death under stress, but its molecular regulation remains unclear.
  • DNA damage triggers complex cellular responses including autophagy, apoptosis, and senescence.
  • The role of specific protein fragments in these stress responses is an active area of research.

Purpose of the Study:

  • To elucidate the function of a proteolytic Cyclin E fragment (p18-CycE) in DNA damage-induced cellular processes.
  • To investigate the signaling pathways linking p18-CycE to autophagy, apoptosis, and senescence.
  • To define the role of p18-CycE in regulating cell fate decisions following DNA damage.

Main Methods:

  • Identification of p18-CycE in hematopoietic cells undergoing DNA damage-induced apoptosis.
  • Analysis of LC3 I/II turnover, autophagosome formation, and autolysosome emergence in epithelial cells with chronic p18-CycE expression.
  • Investigation of the role of ataxia-telangiectasia-mutated (ATM) and adenosine-mono-phosphate-dependent kinase (AMPK) signaling pathways.
  • Assessment of p18-CycE degradation via autophagy and its impact on senescence and apoptosis induction.
  • Examination of p18-CycE and Ku70 co-localization and degradation.

Main Results:

  • Chronic p18-CycE expression induces autophagy, evidenced by increased LC3 I/II turnover and autophagosome/autolysosome formation.
  • p18-CycE activates ATM and AMPK signaling, leading to sustained ULK1 activation, a key autophagy initiator.
  • p18-CycE is degraded through autophagy, promoting senescence; inhibiting autophagy stabilizes p18-CycE, leading to apoptosis.
  • Senescence involves cytoplasmic co-localization and degradation of p18-CycE and Ku70.

Conclusions:

  • Chronic p18-CycE expression initiates autophagy, which clears p18-CycE and induces senescence after DNA damage.
  • Autophagy inhibition stabilizes the p18-CycE-Ku70 complex, promoting apoptosis, thus highlighting a critical role in cell fate determination.
  • These findings reveal a novel mechanism by which DNA damage and apoptotic stress regulate autophagy, senescence, and apoptosis for cell survival.

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