Caspase-dependent apoptosis induced by telomere cleavage and TRF2 loss

Chromosomal abnormalities involving telomeric associations (TAs) often prec ede replicative senescence and abnormal chromosome configurations. We repor t here that telomere cleavage following exposure to pro-apoptotic agents is an early event in apoptosis, Exposure of human and murine cancer cells to a variety of pro-apoptotic stimuli (staurosporine, thapsigargin, anti-fas a ntibody, and cancer chemotherapeutic agents) resulted in telomere cleavage and aggregation, and finally their extrusion from the nuclei. Telomere loss was associated with arrest of cells in G(2)/M phase and preceded DNA fragm entation. Telomere erosion and subsequent large-scale chromatin cleavage we re inhibited by overexpression of the anti-apoptotic protein, bcl-2, and tw o peptide caspase inhibitors (BACMK and zVADfmk), indicating that both even ts are regulated by caspase activation. The results demonstrate that telome re cleavage is an early chromatin alteration detected in various cancer cel l lines leading to drug-induced apoptosis, and suggest that this event cont ributes to mitotic catastrophe and induction of cell death. Results also su ggest that the decrease of telomeric-repeat binding factor 2 (TRF2) may be the earliest event in the ara-C-induced telomere shortening, induction of e ndoreduplication and chromosomal fragmentation leading to cell death.