Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a

Utz Herbig, Wendy A. Jobling, Benjamin P C Chen, David J. Chen, John M. Sedivy

Research output: Contribution to journalArticlepeer-review

839 Scopus citations

Abstract

Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals.

Original languageEnglish (US)
Pages (from-to)501-513
Number of pages13
JournalMolecular cell
Volume14
Issue number4
DOIs
StatePublished - May 21 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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