Telomerase abrogates aneuploidy‐induced telomere replication stress, senescence and cell depletion
Open accessAbstract
The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy‐controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb‐dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase‐deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy‐induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction.
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Telomerase expression in cells arrested due to OIS resolves existing telomere damage and prevents further telomere dysfunction in these cells.
“recent studies have demonstrated that telomerase expression in cells arrested due to OIS is capable of resolving existing telomere damage, and prevents further telomere dysfunction in these cells.”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Meena et al., 2015
Telomerase alleviates telomere damage resulting from replication stress in pre-malignant cells, allowing these cells to escape senescence and contribute to cancer progression.
“Therefore, telomerase alleviates telomere damage as a result of replication stress in pre-malignant cells, allowing these cells to escape senescence, and contribute to cancer progression (Meena et al., 2015, Patel et al., 2016).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Meena et al., 2015
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Cites
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- Authors
- Meena, J. K., Cerutti, A., Beichler, C., Morita, Y., Bruhn, C., Kumar, M., Kraus, J. M., Speicher, M. R., Wang, Z., Kestler, H. A., d'Adda di Fagagna, F., Günes, C., & Rudolph, K. L.
- Affiliations
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- IFOM (IT)
- Medical University of Graz (AT)
- Universität Ulm (DE)
- Corresponding author
- Rudolph, Karl Lenhard
- ORCID
- Venue
- The EMBO Journal
- Published
- 2015-03-27
- Volume
- 34
- Issue
- 10
- Pages
- 1371-1384
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5623828
- OpenAlex
- W1990909310
- Cited by
- 87
- References
- 11
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 7 · 2020: 5 · 2019: 12 · 2018: 12 · 2017: 10 · 2016: 10 · 2015: 2
- FWCI
- 8.35
- Type
- journal article
- Language
- en
- Update notices
- Open access
- hybrid
- doi.org
- Locations
- The EMBO Journal (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- Funders
- Erich und Gertrud Roggenbuck Stiftung and Deutsche Krebshilfe (10‐2086‐Gü 2)
- FP7 PEOPLE 2012 ITN (316354)
- European Research Council (323136, 322726)
- Austrian Science Fund (P23284)
- Associazione Italiana per la Ricerca sul Cancro (8866)
- Human Frontier Science Program (RGP 0014/2012)
- Association for International Cancer Research (14–1331)
- Telethon (GGP12059)
- PRIN (2010–2011)
- Italian Ministry of Education, Universities, and Research (2010M4NEFY_006)
- EPIGEN Project
- FIRC Fellowship
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- telomerase, aneuploidy, premature senescence, hematopoietic stem cells, p53 activation, Rb, telomere length, tumor initiation, fibroblasts
- MeSH terms
- Aneuploidy, Animals, DNA Replication, Hematopoietic Stem Cells, Humans, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Telomerase, Mice
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