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Stable cellular senescence is associated with persistent DDR activation.

Marzia Fumagalli1, Francesca Rossiello1, Chiara Mondello2

  • 1IFOM Foundation - FIRC Institute of Molecular Oncology Foundation, Milan, Italy.

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|October 24, 2014
PubMed
Summary

Cellular senescence involves persistent DNA damage response (DDR) activation, crucial for its establishment and maintenance. Some cell strains show apparent DDR loss due to poor viability under prolonged culture stress.

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Area of Science:

  • Cellular and Molecular Biology
  • Aging Research
  • Genetics and Epigenetics

Background:

  • Cellular senescence is a state of permanent cell cycle arrest.
  • Persistent DNA damage response (DDR) activation is a hallmark of cellular senescence.
  • The long-term dynamics of DDR activation in senescence are debated.

Purpose of the Study:

  • To investigate the dynamics of DNA damage response (DDR) activation in senescent cells over time.
  • To reconcile conflicting reports on DDR persistence in cellular senescence.
  • To understand the role of DDR in the establishment and maintenance of senescence.

Main Methods:

  • Analysis of DDR markers in human fibroblasts at various time points post-senescence induction.
  • Comparison of DDR dynamics in different human cell strains.
  • Assessment of cell viability in relation to DDR status during prolonged in vitro culture.

Main Results:

  • Normal human fibroblasts retain DDR markers for months to years after replicative senescence.
  • Some cell strains exhibit an apparent loss of DDR markers over time, correlating with reduced viability.
  • This apparent DDR loss is attributed to selective cell death in stressed cultures.

Conclusions:

  • Robust DDR activation persists for years in viable senescent cells, supporting its causal role in senescence.
  • Apparent DDR loss in some strains reflects culture-induced stress and selective cell death, not a true loss of DDR.
  • A model reconciling DDR persistence and apparent loss is proposed based on cell viability and culture conditions.