Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling

A Satyanarayana1, R A Greenberg, S Schaetzlein

  • 1Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Germany.

Insights

Replicative senescence signaling is low in quiescent cells but fully activates upon cell cycle entry. DNA damage signals are only triggered by mitogen stimulation in cells with shortened telomeres.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Replicative senescence, triggered by telomere shortening, limits primary cell proliferation.
  • Understanding senescence requires examining its activity within the cell cycle context.

Purpose of the Study:

  • To characterize replicative senescence signaling in quiescent vs. growth-stimulated cells.
  • To investigate DNA damage signaling in senescent cells upon cell cycle induction.

Main Methods:

  • Analysis of senescence phenotypes and signaling pathways in human fibroblasts (in vitro) and liver cells (in vivo).
  • Comparison of quiescent and growth-stimulated cells with shortened telomeres.

Main Results:

  • Senescence signaling is low in quiescent cells with shortened telomeres, but fully activates upon cell cycle stimulation.
  • Dysfunctional telomeres and DNA lesions do not signal damage unless cells are mitogen-stimulated.
  • Mitogen stimulation amplifies senescence and DNA damage responses via MEK/MAPK pathway.

Conclusions:

  • Replicative senescence signaling is cell cycle-dependent.
  • Cell cycle entry is crucial for activating senescence and DNA damage responses in cells with telomere dysfunction.
  • Findings advance understanding of replicative senescence and its in vivo relevance.

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