The mechanism by which telomeres prevent end-to-end fusion has remained elusive. Here, we show that human telomeric protein TRF2 plays a key role in the protective activity of telomeres. A dominant nega- fusions detectable in metaphase and anaphase cells. Telomeric DNA persisted at the fusions, demonstra- ting that TTAGGG repeats per se are not sufficient for telomere integrity. Molecular analysis suggested that the fusions represented ligation of telomeres that have senes 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 senes- cence in primary human cells may be caused by loss by TRF2 from shortened telomeres.