Persistent telomere cohesion protects aged cells from premature senescence

Nat Commun. 2020 Jul 3;11(1):3321. doi: 10.1038/s41467-020-17133-4.

Abstract

Human telomeres are bound by the telomere repeat binding proteins TRF1 and TRF2. Telomere shortening in human cells leads to a DNA damage response that signals replicative senescence. While insufficient loading of TRF2 at shortened telomeres contributes to the DNA damage response in senescence, the contribution of TRF1 to senescence induction has not been determined. Here we show that counter to TRF2 deficiency-mediated induction of DNA damage, TRF1 deficiency serves a protective role to limit induction of DNA damage induced by subtelomere recombination. Shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion. Our findings suggest that the persistent cohesion protects short telomeres from inappropriate recombination. Ultimately, in the final division, telomeres are no longer able to maintain cohesion and subtelomere copying ensues. Thus, the gradual loss of TRF1 and concomitant persistent cohesion that occurs with telomere shortening ensures a measured approach to replicative senescence.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Cell Line
  • Cell Line, Tumor
  • Cellular Senescence / genetics
  • DNA Damage
  • HEK293 Cells
  • Heterochromatin / genetics
  • Heterochromatin / metabolism
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mutation
  • RNA Interference
  • Tankyrases / metabolism
  • Telomere / genetics*
  • Telomere / metabolism
  • Telomere Shortening / genetics*
  • Telomeric Repeat Binding Protein 1 / deficiency
  • Telomeric Repeat Binding Protein 1 / genetics*
  • Telomeric Repeat Binding Protein 1 / metabolism
  • Telomeric Repeat Binding Protein 2 / deficiency
  • Telomeric Repeat Binding Protein 2 / genetics*
  • Telomeric Repeat Binding Protein 2 / metabolism

Substances

  • Heterochromatin
  • TERF2 protein, human
  • Telomeric Repeat Binding Protein 1
  • Telomeric Repeat Binding Protein 2
  • Tankyrases