TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis

Mol Cell Biol. 2009 Mar;29(6):1608-25. doi: 10.1128/MCB.01339-08. Epub 2009 Jan 5.

Abstract

TRF1 is a component of the shelterin complex at mammalian telomeres; however, a role for TRF1 in telomere biology in the context of the organism is unclear. In this study, we generated mice with transgenic TRF1 expression targeted to epithelial tissues (K5TRF1 mice). K5TRF1 mice have shorter telomeres in the epidermis than wild-type controls do, and these are rescued in the absence of the XPF nuclease, indicating that TRF1 acts as a negative regulator of telomere length by controlling XPF activity at telomeres, similar to what was previously described for TRF2-overexpressing mice (K5TRF2 mice). K5TRF1 cells also show increased end-to-end chromosomal fusions, multitelomeric signals, and increased telomere recombination, indicating an impact of TRF1 on telomere integrity, again similar to the case in K5TRF2 cells. Intriguingly, K5TRF1 cells, but not K5TRF2 cells, show increased mitotic spindle aberrations. TRF1 colocalizes with the spindle assembly checkpoint proteins BubR1 and Mad2 at mouse telomeres, indicating a link between telomeres and the mitotic spindle. Together, these results demonstrate that TRF1, like TRF2, negatively regulates telomere length in vivo by controlling the action of the XPF nuclease at telomeres; in addition, TRF1 has a unique role in the mitotic spindle checkpoint.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • DNA Damage / physiology*
  • DNA-Binding Proteins / metabolism
  • Endonucleases / metabolism
  • Epidermal Cells
  • Epidermis / physiology*
  • Epithelium / physiology
  • Homeostasis
  • Keratinocytes / cytology
  • Keratinocytes / physiology*
  • Mad2 Proteins
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mitosis / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Spindle Apparatus / physiology
  • Telomere / physiology*
  • Telomeric Repeat Binding Protein 1 / genetics
  • Telomeric Repeat Binding Protein 1 / physiology*
  • Telomeric Repeat Binding Protein 2 / metabolism

Substances

  • Bub1b protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Mad2 Proteins
  • Mad2l1 protein, mouse
  • TRF2 protein, mouse
  • Telomeric Repeat Binding Protein 1
  • Telomeric Repeat Binding Protein 2
  • Bub1 spindle checkpoint protein
  • Protein-Serine-Threonine Kinases
  • Endonucleases
  • Ercc1 protein, mouse