A two-step model for senescence triggered by a single critically short telomere
Open accessAbstract
Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. 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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A single DNA double-strand break is sufficient to cause full cell cycle blockade.
“Even a single DSB suffices to cause full-blown cell cycle blockade13.”
From The central role of DNA damage in the ageing process (2021) · cites this paper as [13]
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- Authors
- Abdallah, P., Luciano, P., Runge, K. W., Lisby, M., Géli, V., Gilson, E., & Teixeira, M. T.
- Affiliations
- Lyon 1 Université (FR)
- Centre National de la Recherche Scientifique (FR)
- Cleveland Clinic (US)
- University of Copenhagen (DK)
- Venue
- Nature Cell Biology
- Published
- 2009-07-13
- Volume
- 11
- Issue
- 8
- Pages
- 988-993
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4025917
- OpenAlex
- W2085494245
- Cited by
- 190
- References
- 34
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 11 · 2023: 12 · 2022: 6 · 2021: 11 · 2020: 7 · 2019: 10 · 2018: 10 · 2017: 10 · 2016: 13 · 2015: 9 · 2014: 12 · 2013: 14 · 2012: 13
- FWCI
- 10.42
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-05-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institute on Aging (R01AG019960)
- National Institute of General Medical Sciences (R01GM050752)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- replicative senescence, telomere length, telomerase deficiency, RAD52, DNA damage signaling, telomere shortening, chromosome end protection
- MeSH terms
- Cell Cycle, Cell Division, DNA Nucleotidyltransferases, Models, Biological, Mutation, Protein Binding, Saccharomyces cerevisiae, Spores, Fungal, Signal Transduction, Telomere, Protein Serine-Threonine Kinases, Telomerase, Saccharomyces cerevisiae Proteins, Intracellular Signaling Peptides and Proteins, Rad52 DNA Repair and Recombination Protein
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