Telomere uncapping in progenitor cells with critical telomere shortening is coupled to S-phase progression in vivo
Open accessAbstract
Telomeres protect chromosome ends and serve as a substrate for telomerase, a reverse transcriptase that adds DNA repeats to the telomere terminus. In the absence of telomerase, telomeres progressively shorten, ultimately leading to telomere uncapping, a structural change at the telomere that activates DNA damage responses and leads to ligation of chromosome ends. Telomere uncapping has been implicated in aging and cancer, yet the precise mechanism of uncapping and its relationship to cell cycle remain to be defined. Here, we show that telomeres uncap in an S-phase-dependent manner in gastrointestinal progenitors of TERT(-/-) mice. We develop an in vivo assay that allows a quantitative kinetic assessment of telomere dysfunction-induced apoptosis and its relationship to cell cycle. By exploiting the mathematical relationship between rates of generation and clearance of apoptotic cells, we show that 86.2 +/- 8.8% of apoptotic gastrointestinal cells undergo programmed cell death either late in S-phase or in G2. Apoptosis is primarily triggered via a signaling cascade from newly uncapped telomeres to the tumor suppressor p53, rather than by chromosome fusion-bridge breakage, because mitotic blockade did not alter the rate of newly generated apoptotic bodies. These data support a model in which rapidly dividing progenitor cells within a tissue with short telomeres are vulnerable to telomere uncapping during or shortly after telomere replication.
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Dysfunctional telomeres can also activate p53-dependent apoptosis, since mice bearing dysfunctional telomeres show increased apoptosis in proliferative cells.
“In addition to promoting cell cycle arrest, dysfunctional telomeres can also activate p53-dependent apoptosis, since mice bearing dysfunctional telomeres show increased apoptosis in proliferative cells31-33.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [33]
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How Somatic Mutations cause Aging without Causing AgingPreprint
Wolf, A. M. (2026) · SSRN Electronic Journal · doi:10.2139/ssrn.6431458
- Authors
- Rajaraman, S., Choi, J., Cheung, P., Beaudry, V., Moore, H., & Artandi, S. E.
- Affiliations
- *Department of Medicine and
- Stanford Medicine (US)
- Genentech (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-11-06
- Volume
- 104
- Issue
- 45
- Pages
- 17747-17752
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2077026
- OpenAlex
- W2021046086
- Cited by
- 44
- References
- 41
- Citations by year
- 2026: 2 · 2023: 1 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 3
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK56339)
- Samsung
- National Cancer Institute (R01CA111691)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056339, P30DK56339)
- 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 › Cell death mechanisms and regulation
- Keywords
- telomere uncapping, telomere shortening, telomerase deficiency, S phase progression, apoptosis, p53 pathway, telomere dysfunction, cell cycle, telomere replication, DNA damage response
- MeSH terms
- Animals, Bromodeoxyuridine, Crosses, Genetic, DNA Damage, Intestinal Mucosa, Models, Genetic, Stem Cells, Tumor Suppressor Protein p53, G2 Phase, S Phase, Telomere, Apoptosis, Mice, Knockout, Telomerase, In Situ Nick-End Labeling, Mice
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