| While telomerase deficiency is known to elicit cell cycle arrest and apoptosis, the specific mechanisms by which global telomere shortening results in these cellular defects has remained unclear. The following work was performed to examine both the proximate causes and the specific consequences of telomere dysfunction resulting from telomere shortening. The results suggest that the absence of telomerase, per se, has no global effect on telomere end structures. Mouse phenotypes associated with telomere shortening occurred due to the presence of individual critically shortened telomeres. These critically shortened telomeres were recognized as DNA double-strand breaks, eliciting an apoptotic response in some situations and processed by non-homologous end-joining into chromosome fusions in other situations. Elongation of critically short telomeres by the reintroduction of telomerase, despite a short average telomere length, resulted in the complete absence of phenotypes associated with telomere dysfunction. That telomere function is preserved by the presence of a minimum telomere length on all chromosome ends, rather than a specific average telomere length was supported by a more general analysis of mouse telomere length regulation. Average telomere length varied considerably between very similar strains of mouse, revealing a disconnect between the maintenance of average telomere length and the determinants of telomere function. Additionally, in inter-species crosses between mice with long average telomere length and mice with short average telomere length, only the shortest telomeres were elongated in the progeny, again indicating that the maintenance of global telomere function occurs via the elongation of only the shortest telomeres. This data suggests that, rather than the average telomere length, the propagation of cells or organisms in the absence of telomerase is limited by the shortest telomeres in a distribution of telomere lengths. |
