A switch-like dynamic mechanism for the initiation of replicative senescence

FEBS Lett. 2014 Nov 28;588(23):4369-74. doi: 10.1016/j.febslet.2014.09.043. Epub 2014 Oct 12.


Telomeres are specialized structures protecting chromosomes against genome instability. Telomeres shorten with cell division, and replicative senescence is induced when telomeres are badly eroded. Whereas TRF2 (telomeric-repeat binding factor 2), ATM (ataxia telangiectasia mutated) and p53 have been identified involved in senescence induction, how it is triggered remains unclear. Here, we propose an integrated model associating telomere loss with senescence trigger. We characterize the dynamics of telomere shorting and the p53-centered regulatory network. We show that senescence is initiated in a switch-like manner when both the shortest telomere becomes uncapped and the TRF2-ATM-p53-Siah1 positive feedback loop is switched on. This work provides a coherent picture of senescence induction in terms of telomere shortening and p53 activation.

Keywords: Bistable switch; Regulatory network; Replicative senescence; Telomere shortening; p53 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Diploidy
  • Down-Regulation
  • Feedback, Physiological
  • Fibroblasts / cytology
  • Humans
  • Models, Biological*
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Telomere Shortening*
  • Telomeric Repeat Binding Protein 2 / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / metabolism


  • Nuclear Proteins
  • Telomeric Repeat Binding Protein 2
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • Ataxia Telangiectasia Mutated Proteins