Telomere and genome instability in yeast

In the absence of telomerase, telomere shortening triggers the DNA damage checkpoint and replicative senescence, a potent tumor suppressor mechanism that is also associated with oncogenic genomic instability. To directly study the complex interplay between senescence, telomere dynamics, and genomic instability, we developed a system in Saccharomyces cerevisiae to generate and track the dynamics of telomeres of precise length in the absence of telomerase. Using single-telomere and single-cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly in cis to the shortest telomere as non-reciprocal translocations that result in re-elongation of the shortest telomere and escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival, explaining the contradictory roles of replicative senescence in oncogenesis.