Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells
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.
Authors
- Karine Casier (ORCID: https://orcid.org/0000-0001-6825-8057)
- Anaïs Rat (ORCID: https://orcid.org/0000-0001-5174-6329)
- Théo Aspert (ORCID: https://orcid.org/0000-0003-2957-0683)
- Pascale Jolivet (ORCID: https://orcid.org/0000-0002-3896-0598)
- Prisca Berardi
- Alexandre Maes (ORCID: https://orcid.org/0000-0002-7966-1340)
- Hinke G. Kazemier
- Maria Teresa Teixeira (ORCID: https://orcid.org/0000-0002-9466-7951)
- Stefano Mattarocci (ORCID: https://orcid.org/0000-0002-5105-6018)
- Bechara Zeinoun
- Marie Doumic
- Fernando R. Rosas Bringas
- Veronica Martinez-Fernandez
- Gilles Charvin
- Rachel Langston
- Michael Chang
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- University Medical Center Groningen (NL)
- École Polytechnique (FR)
- Inserm (FR)
- Université de Bretagne Occidentale (FR)
- University of Groningen (NL)
- Sorbonne Université (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Laboratoire de Mathématiques de Bretagne Atlantique (FR)
- Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes (FR)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-15
- DOI
- https://doi.org/10.1038/s41467-026-70352-z
- Citations
- 1
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 32.84
Funders
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Consejo Nacional de Ciencia y Tecnología
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Ligue Contre le Cancer
- Institut National Du Cancer
- Fondazione Regionale per la Ricerca Biomedica