Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells
Abstract
In the absence of telomerase, telomere shortening triggers replicative senescence, a tumor suppressor mechanism that 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 develop a system in Saccharomyces cerevisiae to generate and track 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 Pol32-dependent non-reciprocal translocations that result in re-elongation of the shortest telomere and likely transient 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.
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BibTeX
@article{berardi2026both,
title = {{Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells}},
author = {Prisca Berardi and Veronica Martinez-Fernandez and Anaïs Rat and Fernando R Rosas Bringas and Pascale Jolivet and Rachel Langston and Stefano Mattarocci and Alexandre Maes and Théo Aspert and Bechara Zeinoun and Karine Casier and Hinke G Kazemier and Gilles Charvin and Marie Doumic and Michael Chang and Maria Teresa Teixeira},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-70352-z},
url = {https://hal.science/hal-05731904v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells
AU - Prisca Berardi
AU - Veronica Martinez-Fernandez
AU - Anaïs Rat
AU - Fernando R Rosas Bringas
AU - Pascale Jolivet
AU - Rachel Langston
AU - Stefano Mattarocci
AU - Alexandre Maes
AU - Théo Aspert
AU - Bechara Zeinoun
AU - Karine Casier
AU - Hinke G Kazemier
AU - Gilles Charvin
AU - Marie Doumic
AU - Michael Chang
AU - Maria Teresa Teixeira
PY - 2026
DA - 2026/08/31
JO - Nature Communications
DO - 10.1038/s41467-026-70352-z
UR - https://hal.science/hal-05731904v1
AB - In the absence of telomerase, telomere shortening triggers replicative senescence, a tumor suppressor mechanism that 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 develop a system in Saccharomyces cerevisiae to generate and track 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 Pol32-dependent non-reciprocal translocations that result in re-elongation of the shortest telomere and likely transient 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.
SN - 2041-1723
SN - 2041-1723
ER -