Disappearance of the Telomere Dysfunction-Induced Stress Response in Fully Senescent Cells
Abstract
Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Here, we demonstrate that ATM activation and H2AX-γ nuclear focus formation are sensitive markers of telomere dysfunction in primary human fibroblasts. Whereas the activated form of ATM and H2AX-γ foci were rarely observed in early-passage cells, they were readily detected in late-passage cells. The ectopic expression of telomerase in late-passage cells abrogated ATM activation and H2AX-γ focus formation, suggesting that these stress responses were the consequence of telomere dysfunction. ATM activation was induced in quiescent fibroblasts by inhibition of TRF2 binding to telomeres, indicating that telomere uncapping is sufficient to initiate the telomere signaling response; breakage of chromosomes with telomeric associations is not required for this activation. Although ATM activation and H2AX-γ foci were readily observed in late-passage cells, they disappeared once cells became fully senescent, indicating that constitutive signaling from dysfunctional telomeres is not required for the maintenance of senescence.
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Detection of the DDR is often lost once cellular senescence is induced.
“Detection of the DDR is often lost once cellular senescence is induced [5, 40].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [5]
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“Interestingly, the slow process of active DDR diminution in the tissue resembles the in vitro phenomenon of long term (or “deep”) senescence of fibroblasts, where with time there is loss of 53BP1, phospho ATM, total p53, and/or phospho p53 (S15) induction in individual cells after entry into the senescent state (Bakke…”
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“Once initiated, SAHF may become self-sustaining and thereby no longer require the presence of either DNA damage or cell cycle inhibitors to maintain the senescent nondividing state (Bakkenist et al. 2004).”
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TRANSCRIPTOME STUDIES OF CELL-FATE AND AGING
Larsson, O. S. (2005) · Figshare
The effect of radiation on cellular ageing
Sabin, R. J. (2012) · Brunel University Research Archive (BURA) (Brunel University London)
Spagnoli, L. G., Mauriello, A., Orlandi, A., Scimeca, M., Volpe, A., & Bonanno, E. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-381510-1.00105-8
Aging and Senescence Studies in Human and Zebrafish
Hirata, H., Tezuka, T., & Ujibe, K. (2024) · Current topics in environmental health and preventive medicine · doi:10.1007/978-981-97-2712-4_1
- Authors
- Bakkenist, C. J., Drissi, R., Wu, J., Kastan, M. B., & Dome, J. S.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Venue
- Cancer Research
- Published
- 2004-06-01
- Volume
- 64
- Issue
- 11
- Pages
- 3748-3752
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2109369265
- Cited by
- 68
- References
- 20
- Citations by year
- 2024: 1 · 2023: 3 · 2022: 1 · 2021: 3 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 4
- FWCI
- 4.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- California Institute of Technology
- National Cancer Institute (CA71387, CA21765, R01CA071387, P30CA021765)
- 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
- telomere dysfunction, replicative senescence, ATM activation, telomerase, TRF2, telomere uncapping, DNA damage response, human fibroblasts
- MeSH terms
- Cell Nucleus, Cells, Cultured, DNA-Binding Proteins, Fibroblasts, HeLa Cells, Histones, Humans, Microscopy, Fluorescence, Signal Transduction, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Ataxia Telangiectasia Mutated Proteins
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