Abstract
Telomeres protect chromosome ends from fusion and degradation1. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence2. Here, we show that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence. We further show that Mec1p–ATR specifically recognizes the single, very short telomere causing the accelerated senescence. Strikingly, before entering senescence, cells divide for several generations despite complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 (radiation sensitive) and MMS1 (methyl methane sulfonate sensitive), and there is no evidence for major inter-telomeric recombination. We propose that, in the absence of telomerase, a very short telomere is first maintained in a pre-signalling state by a RAD52–MMS1-dependent pathway and then switches to a signalling state leading to senescence through a Mec1p-dependent checkpoint.
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Change history
24 March 2010
In the version of this letter initially published online, the labels '0 block' and '2 block' in Fig. 2a were swapped. This error has been corrected in both the HTML and PDF versions of the article.
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Acknowledgements
We thank R. Wellinger and L. Rudolph for fruitful suggestions, G. Yvert and C. Lopes for advice in statistical analysis and A. Jacquier for sharing unpublished material. We also thank T. Petes, M. P. Longhese and S. Marcand for strains and plasmids. P.A. gratefully acknowledges the financial support of the Lebanese National council for Scientific Research (CNRSL) and the Association pour la Recherche sur le Cancer (ARC). This work was supported by La Ligue Contre le Cancer (E.G. and V.G., équipes labellisées), the INCa programmes TELINCA and TELOFUN (E.G. and V.G.), The Danish Agency for Science, Technology and Innovation (M.L.), the Villum Kann Rasmussen Foundation (M.L.) and the National Institutes of Health (K.R.).
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P.A., P.L. and M.T.T. carried out and analysed the experiments. E.G. and M.T.T. designed and directed the project with the contribution of K.W.R., M.L. and V.G.
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Abdallah, P., Luciano, P., Runge, K. et al. A two-step model for senescence triggered by a single critically short telomere. Nat Cell Biol 11, 988–993 (2009). https://doi.org/10.1038/ncb1911
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DOI: https://doi.org/10.1038/ncb1911
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