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Different telomere damage signaling pathways in human and mouse cells
Open accessAbstract
Programmed telomere shortening in human somatic cells is thought to act as a tumor suppressor pathway, limiting the replicative potential of developing tumor cells. Critically short human telomeres induce senescence either by activating p53 or by inducing the p16/RB pathway, and suppression of both pathways is required to suppress senescence of aged human cells. Here we report that removal of TRF2 from human telomeres and the ensuing de-protection of chromosome ends induced immediate premature senescence. Although the telomeric tracts remained intact, the TRF2(DeltaBDeltaM)-induced premature senescence was indistinguishable from replicative senescence and could be mediated by either the p53 or the p16/RB pathway. Telomere de-protection also induced a growth arrest and senescent morphology in mouse cells. However, in this setting the loss of p53 function was sufficient to completely abrogate the arrest, indicating that the p16/RB response to telomere dysfunction is not active in mouse cells. These findings reveal a fundamental difference in telomere damage signaling in human and mouse cells that bears on the use of mouse models for the telomere tumor suppressor pathway.
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“Consistent with previous reports (27), G4 mTerc -/ -Ink4a / Arf -/ -MEFs showed an intermediate phenotype of decreased growth rates after 10 population doublings with steady slow proliferation thereafter, indicating that telomere dysfunction suppresses the growth rate, but not the immortalization potential, of Ink4a / Arf -/ -MEFs.”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [27]
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“In MEFs, p19 Arf and p16 Ink4a contribute to the growth arrest incurred by telomere deprotection (14, 27).”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [27]
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“For example, mouse cells are thought to rely primarily on the p53 pathway for both replicative and telomere-dependent senescence (Harvey et al., 1993; Smogorzewska and de Lange, 2002).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Smogorzewska and de Lange, 2002
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“Consistent with the latter, p19 Arf deficiency has been reported to provide partial rescue of growth arrest after acute deprotection of telomeres by expression of a dominant-negative mutant of the telomere binding protein, Trf2, in mouse embryonic fibroblasts (MEFs) (27).”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [27]
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“By contrast, p53 inactivation alone is sufficient to avoid telomere-induced senescence and apoptosis in mice49,50.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [50]
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“Damaged telomeres eventually register as a form of DNA damage (8) triggering among other things a p53-mediated cell cycle arrest (9).”
From Glycolytic Enzymes Can Modulate Cellular Life Span (2005) · cites this paper as [9]
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Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
“Furthermore, there are species-specific differences: for example, experimental disruption of telomeres primarily engages the p53 pathway in mouse cells but both the p53 and p16–pRB pathways in human cell”
BackgroundShelterin: the protein complex that shapes and safeguards human telomeres
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“…activate the DNA damage response pathway first emerged from experiments in which the shelterin subunit TRF2 was inhibited with a dominant-negative allele (TRF2 B M), that heterodimerizes with the endogenous TRF2, blocking its binding to DNA (van Steensel et al. 1998; for review, see de Lange 2002).”
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,917
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How Shelterin Protects Mammalian Telomeres
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“In fibroblasts, this arrest is accompanied by senescence while in other cell types, the same signaling cascade can induce apoptosis (94, 174, 188).”
Background
Metadata
- Authors
- Smogorzewska, A., & de Lange, T.
- Affiliations
- Rockefeller University (US)
- ORCID
- Smogorzewska, Agata
- Venue
- The EMBO Journal
- Published
- 2002-08-15
- Volume
- 21
- Issue
- 16
- Pages
- 4338-4348
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC126171
- OpenAlex
- W2126815966
- Cited by
- 482
- References
- 55
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 11 · 2023: 9 · 2022: 3 · 2021: 16 · 2020: 10 · 2019: 9 · 2018: 17 · 2017: 13 · 2016: 14 · 2015: 19 · 2014: 14 · 2013: 20 · 2012: 25
- FWCI
- 28.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Institute on Aging (AG 16643)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- premature senescence, TRF2, p53, p16/Rb pathway, replicative senescence, tumor suppressor pathways, human-mouse differences, growth arrest, telomere dysfunction
- MeSH terms
- Animals, Cell Line, Chromosome Aberrations, DNA Damage, DNA-Binding Proteins, Fibroblasts, Humans, Signal Transduction, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Telomeric Repeat Binding Protein 2, Mice
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