Cell cycle arrest in replicative senescence is not an immediate consequence of telomere dysfunction

M.Shamim Nassrally, Ashley Lau, Katherine Wise, Noah John, Sanjeev Kotecha, Kar Lai Lee, Robert F. Brooks

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
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In replicative senescence, cells with critically-short telomeres activate a DNA-damage response leading to cell-cycle arrest, while those without telomere dysfunction would be expected to cycle normally. However, population growth declines more gradually than such a simple binary switch between cycling and non-cycling states would predict. We show here that late-passage cultures of human fibroblasts are not a simple mixture of cycling and non-cycling cells. Rather, although some cells had short cycle times comparable to those of younger cells, others continued to divide but with greatly extended cycle times, indicating a more-gradual approach to permanent arrest. Remarkably, in late passage cells, the majority showed prominent DNA-damage foci positive for 53BP1, yet many continued to divide. Evidently, the DNA-damage-response elicited by critically-short telomeres is not initially strong enough for complete cell-cycle arrest. A similar continuation of the cell cycle in the face of an active DNA-damage response was also seen in cells treated with a low dose of doxorubicin sufficient to produce multiple 53BP1 foci in all nuclei. Cell cycle checkpoint engagement in response to DNA damage is thus weaker than generally supposed, explaining why an accumulation of dysfunctional telomeres is needed before marked cell cycle elongation or permanent arrest is achieved.
Original languageEnglish
Pages (from-to)11-22
Number of pages12
JournalMechanisms of Ageing and Development
Early online date30 Jan 2019
Publication statusPublished - 1 Apr 2019


  • Cell senescence
  • Telomere-dysfunction
  • DNA-damage response
  • 53BP1
  • Clonal heterogeneity


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