Different telomere damage signaling pathways in human and mouse cells

EMBO J. 2002 Aug 15;21(16):4338-48. doi: 10.1093/emboj/cdf433.


Programmed telomere shortening in human somatic cells is thought to act as a tumor suppressor pathway, limiting the replicative potential of developing tumor cells. Critically short human telomeres induce senescence either by activating p53 or by inducing the p16/RB pathway, and suppression of both pathways is required to suppress senescence of aged human cells. Here we report that removal of TRF2 from human telomeres and the ensuing de-protection of chromosome ends induced immediate premature senescence. Although the telomeric tracts remained intact, the TRF2(DeltaBDeltaM)-induced premature senescence was indistinguishable from replicative senescence and could be mediated by either the p53 or the p16/RB pathway. Telomere de-protection also induced a growth arrest and senescent morphology in mouse cells. However, in this setting the loss of p53 function was sufficient to completely abrogate the arrest, indicating that the p16/RB response to telomere dysfunction is not active in mouse cells. These findings reveal a fundamental difference in telomere damage signaling in human and mouse cells that bears on the use of mouse models for the telomere tumor suppressor pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cellular Senescence / physiology
  • Chromosome Aberrations
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA Damage*
  • DNA-Binding Proteins / physiology
  • Fibroblasts
  • Humans
  • Mice
  • Signal Transduction*
  • Telomere / physiology*
  • Telomeric Repeat Binding Protein 2
  • Tumor Suppressor Protein p53 / metabolism


  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • Tumor Suppressor Protein p53