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Updated: Jun 9, 2025

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
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Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence

Leighton H Daigh1, Debarya Saha2, David L Rosenthal2

  • 1Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Nature Communications
|October 25, 2024
PubMed

Insights

Cellular senescence, linked to aging, involves persistent DNA damage. This study reveals mTORC1 signaling drives DNA damage in non-proliferating cells, while E2F activation repairs it, offering anti-aging insights.

Area of Science:

  • Molecular Biology
  • Cellular Aging
  • Genetics

Background:

  • Cellular senescence, a state of irreversible cell cycle arrest, is a hallmark of organismal aging.
  • DNA damage is a known trigger for senescence, but mechanisms maintaining DNA damage in non-proliferating senescent cells are unclear.
  • Understanding senescence is crucial for developing anti-aging therapies.

Purpose of the Study:

  • To investigate the mechanisms by which senescent cells maintain DNA damage.
  • To explore the role of mTORC1 signaling and E2F transcriptional program in senescence.
  • To identify potential targets for anti-aging interventions.

Main Methods:

  • Utilized reversible expression of p16INK4 (p16), a senescence-inducing protein.
  • Employed live single-cell analysis to monitor cellular processes.
  • Investigated the interplay between mTORC1 signaling, DNA damage, inflammation, and E2F activity.

Main Results:

  • Sustained mTORC1 signaling induces senescence in non-proliferating cells by increasing persistent transcriptional DNA damage and inflammation.
  • This damage and inflammation signaling remain even after the senescence inducer (p16) is degraded.
  • Activation of the E2F transcriptional program repairs transcriptionally damaged DNA independently of DNA replication.

Conclusions:

  • Senescence can be perpetuated by ongoing mTORC1-driven transcriptional DNA damage.
  • The E2F transcriptional program plays a critical role in repairing this damage.
  • Targeting mTORC1 and E2F pathways may offer novel anti-aging therapeutic strategies.

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