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Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence

Francesca Rossiello1, Utz Herbig2, Maria Pia Longhese3

  • 1IFOM Foundation - FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.

Current Opinion in Genetics & Development
|August 9, 2014
PubMed

Insights

Cellular senescence, a state of irreversible cell cycle arrest, is linked to aging and DNA damage response (DDR). This study explores the role of telomeric DNA damage in aging and senescence across different cell types.

Area of Science:

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

Background:

  • The DNA damage response (DDR) is crucial for DNA repair and cell cycle regulation.
  • Unresolved DNA damage can lead to cellular senescence, a state of permanent cell cycle arrest.
  • Aging in mammals involves senescence markers and persistent DDR at telomeres, particularly in non-proliferating cells.

Purpose of the Study:

  • To investigate the role of telomeres and telomeric DNA damage in the aging of non-proliferating mammalian cells.
  • To determine if distinct types of cellular senescence share common underlying mechanisms.
  • To elucidate the specific contribution of telomeric DNA damage to cellular senescence.

Main Methods:

  • Analysis of DNA damage response pathways.
  • Telomere length and integrity assessment.
  • Cellular senescence induction and characterization.
  • Investigation of oncogene-induced senescence models.

Main Results:

  • Accumulation of senescence markers and persistent DDR at telomeres are observed in aging mammals.
  • Oncogene activation triggers cellular senescence via altered DNA replication and DDR, particularly at telomeres.
  • Evidence suggests shared mechanisms across different forms of cellular senescence, involving telomeric DNA damage.

Conclusions:

  • Telomeric DNA damage is a key factor in cellular senescence and organismal aging, even in non-proliferating cells.
  • A common mechanistic pathway involving telomeric DDR likely underlies various forms of cellular senescence.
  • Understanding telomeric DNA damage is critical for aging and cancer research.

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