TRF2 Protects Human Telomeres from End-to-End Fusions

Abstract

The mechanism by which telomeres prevent end-to-end fusion has remained elusive. Here, we show that the human telomeric protein TRF2 plays a key role in the protective activity of telomeres. A dominant negative allele of TRF2 induced end-to-end chromosome fusions detectable in metaphase and anaphase cells. Telomeric DNA persisted at the fusions, demonstrating that TTAGGG repeats per se are not sufficient for telomere integrity. Molecular analysis suggested that the fusions represented ligation of telomeres that have lost their single-stranded G-tails. Therefore, TRF2 may protect chromosome ends by maintaining the correct structure at telomere termini. In addition, expression of mutant forms of TRF2 induced a growth arrest with characteristics of senescence. The results raise the possibility that chromosome end fusions and senescence in primary human cells may be caused by loss by TRF2 from shortened telomeres.

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

“…Reduction of the 3 0 overhang and subsequent apoptosis is an effect reminiscent of results obtained for dominantnegative TRF2, which were previously reported by the group of Titia de Lange (van Steensel et al, 1998). Transfection of dominant-negative TRF2, TRF2 DBDM , induces the dissociation of TRF2 protein from telomeres, followed by chromosome fusion, anaphase bridge formation and apoptosis or senescence (van Steensel et al, 1998).…”

“…Transfection of dominant-negative TRF2, TRF2 DBDM , induces the dissociation of TRF2 protein from telomeres, followed by chromosome fusion, anaphase bridge formation and apoptosis or senescence (van Steensel et al, 1998).…”

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…Human 143B parental and rho0 osteosarcoma cells were grown in Dulbecco's modified Eagle's medium (DMEM, Sigma, Dorset, UK) supplemented with 10% heat‐inactivated foetal calf serum (FCS), 100 units ml −1 penicillin, 100 μg ml −1 streptomycin, 2 mM glutamine, 50 μg ml −1 uridine and 0.11 mg ml −1 sodium pyruvate at 37°C in a humidified atmosphere with 5% CO 2 . T19 cells containing a doxycycline‐inducible TRF2 ΔBΔM were a kind gift from T. de Lange, Rockefeller University, NY, USA (van Steensel et al , 1998). AT patient fibroblasts were a kind gift from Dr. Lisa Woodbine, University of Sussex, UK.…”

The significance of telomeric aggregates in the interphase nuclei of tumor cells

“…However, this has not been demonstrated in tumor models. We know from studies of de Lange and colleagues that the absence of TRF2 leads to the formation of telomeric fusions which lead to cell death and senescence [van Steensel et al, 1998;Celli and de Lange, 2005]. Whether these fusions involve TA formation and can be linked to genomic instability and cancer has not been investigated.…”