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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G4 mTerc-/- Ink4a/Arf-/- MEFs showed an intermediate phenotype of decreased growth rates after 10 population doublings with steady slow proliferation thereafter.
“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 <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [27]
The “Mouse telomere damage signaling: p53 alone” section says Ink4a/Arf-deficient cells can continue growing despite telomere dysfunction and that shortened telomeres did not prevent immortalization of late-generation mTerc-deficient MEFs. It does not report growth rates for G4 mTerc−/− Ink4a/Arf−/− MEFs, a decline after 10 population doublings, or steady slow proliferation thereafter. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn MEFs, p19 Arf and p16 Ink4a contribute to the growth arrest incurred by telomere deprotection.
“In MEFs, p19 Arf and p16 Ink4a contribute to the growth arrest incurred by telomere deprotection (14, 27).”
From <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [27]
The section headed “The p19” reports that MEFs lacking p19 Arf failed to arrest normally after Trf2 inhibition, supporting its contribution. But that section also reports that p16-deficient MEFs arrested like wild-type MEFs; “Mouse telomere damage signaling: p53 alone” says p16 was not required for the arrest. Thus the source does not support attributing a contribution to both proteins. (LLM, conf=0.90)
Experimental — accuracy not yet measuredMouse cells are thought to rely primarily on the p53 pathway for both replicative and telomere-dependent senescence.
“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
The section “Mouse telomere damage signaling: p53 alone” concludes that the mouse-cell response to telomere dysfunction is primarily dependent on p53. The Introduction and Discussion describe TRF2-induced arrest as resembling replicative senescence, but do not establish that ordinary replicative senescence in mouse cells primarily relies on p53. (LLM, conf=0.86)
Experimental — accuracy not yet measuredp19Arf deficiency provides partial rescue of growth arrest after acute deprotection of telomeres by expression of a dominant-negative mutant of Trf2 in mouse embryonic fibroblasts.
“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 <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [27]
In mice, p53 inactivation alone is sufficient to avoid telomere-induced senescence and apoptosis.
“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]
Damaged telomeres trigger a p53-mediated cell cycle arrest.
“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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BackgroundTelomerase induces immortalization of human esophageal keratinocytes without p16INK4a inactivation.
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“In addition, other types of stress have been found to up-regulate the expression of the Ink4a/Arf locus, such as prolonged cultivation in the absence of an appropriate extracellular matrix (Ramirez et al. 2001) or telomere dysfunction (Smogorzewska and de Lange 2002).”
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“This leads to a slow decrease in telomere size, loss of terminal DNA structures and the consequent DNA-DAMAGE CHECKPOINTS that put a stop to TELOMERIC TRACT ATTRITION and cell growt”
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- 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
- Health Sciences › Medicine › Physiology › 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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