The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo

Telomere dysfunction induces two types of cellular response: cellular senescence and apoptosis. We analysed the extent to which the cellular level of telomere dysfunction and p53 gene status affect these cellular responses in mouse liver using the experimental system of TRF2 inhibition by a dominant-negative version of the protein (TRF2(DeltaBDeltaM)). We show that the level of telomere dysfunction correlates with the level of TRF2(DeltaBDeltaM) protein expression resulting in chromosomal fusions, aberrant mitotic figures and aneuploidy of liver cells. These alterations provoked p53-independent apoptosis, but a strictly p53-dependent senescence response in distinct populations of mouse liver cells depending on the cellular level of TRF2(DeltaBDeltaM) expression. Apoptosis was associated with higher expression of TRF2(DeltaBDeltaM), whereas cellular senescence was associated with low levels of TRF2(DeltaBDeltaM) expression. Our data provide experimental evidence that induction of senescence or apoptosis in vivo depends on the cellular level of telomere dysfunction and differentially on p53 gene function.