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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Data availability
The microfluidics chip design and movies generated in this study have been deposited in Zenodo (https://doi.org/10.5281/zenodo.13821423)101. The sequencing data generated in this study have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI under accession number PRJEB80380. Source data are provided with this paper.
Code availability
Codes for mathematical modeling are available at GitHub (https://github.com/anais-rat/telomeres)102. The Geneious Prime 2023.2.1 workflows for individual telomere sequence analysis, along with the MATLAB code for mutation rate calculation from fluctuation assays, are available on Zenodo (https://doi.org/10.5281/zenodo.13821423)101.
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Acknowledgements
We wish to thank E. Fabre and V. Borde for sharing technical advice, Z. Xu for first mathematical simulations and fluctuation assay code and M. Godinho Ferreira, C. Azzalin, B. Llorente and G. Fischer for fruitful discussion. We also acknowledge J. Haber, H. Ulrich, M. Lisby for strains and plasmids and Virgile Andreani for improvements with codes. We also thank the Teixeira lab, numerous trainees and the UMR8226 unit members for technical support and fruitful discussions. We also thank T. Weinert, D. Kappei, E. Fabre, and M. Bao (Life Science Editors) for critical reading of the manuscript. P.B. was supported by a fellowship from the Ligue Contre le Cancer (France), F.R.R.B. was supported by a “Consejo Nacional de Ciencia y Tecnología” (CONACYT) scholarship and K.C. was supported by a fellowship from “Fondation pour la Recherche Médicale” (FRM). Work in M.C. lab was supported by an Open Competition M-2 grant from the Dutch Research Council. The work conducted in the MTT laboratory was funded by the Fondation pour la Recherche Médicale (FRM) through its “Équipe Labellisée” program and by the French National Research Agency (ANR) under the “Investissements d’Avenir” initiative (LabEx Dynamo, ANR-11-LABX-0011-01). The M.T.T. and M.D. laboratories also receive support from the ANR as part of the France 2030 program (23-EXMA-0005). Additionally, the M.T.T., G.C., and M.D. teams are funded by the ANR (ANR-16-CE12-0026) and the Institut National du Cancer (PLBIO20−312).
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Berardi, P., Martinez-Fernandez, V., Rat, A. et al. Both genome instability and replicative senescence stem from the shortest telomere in telomerase-negative cells. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70352-z
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DOI: https://doi.org/10.1038/s41467-026-70352-z
