Pré-Publication, Document De Travail Année : 2025

The shortest telomere in telomerase-negative cells triggers replicative senescence at a critical threshold length and also fuels genomic instability

Karine Casier

Résumé

In the absence of telomerase, telomere shortening triggers the DNA damage checkpoint and replicative senescence, a potent tumor suppressor mechanism. Paradoxically, this same process is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. 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 likely 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.

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hal-04926171 , version 1 (26-02-2025)

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Prisca Berardi, Veronica Martinez Fernandez, Anaïs Rat, Fernando Rosas Bringas, Pascale Jolivet, et al.. The shortest telomere in telomerase-negative cells triggers replicative senescence at a critical threshold length and also fuels genomic instability. 2024. ⟨hal-04926171⟩
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