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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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Wyatt, H. D. M., West, S. C., & Beattie, T. L. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq370 · Cited by 190
POT1 and TRF2 Cooperate To Maintain Telomeric Integrity
Yang, Q., Zheng, Y., & Harris, C. C. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.3.1070-1080.2005 · Cited by 190
“Loss of telomeric overhang can induce a premature senescent phenotype in primary fibroblasts (45, 52).”
BackgroundResultInfluentialTargeted Deletion Reveals an Essential Function for the Telomere Length Regulator Trf1
Karlseder, J., Kachatrian, L., Takai, H., Mercer, K. L., Hingorani, S. R., Jacks, T., & de Lange, T. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.18.6533-6541.2003 · Cited by 181
“For instance, the phenotype of telomere shortening in Terc / mice can be partially suppressed by p53 deficiency, and the growth arrest induced by telomere uncapping is eliminated in p53 / MEFs (2, 14, 50).”
BackgroundInfluentialTelomeres and chromosome instability
Murnane, J. P. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.05.030 · Cited by 178
Mitochondria, telomeres and cell senescence: Implications for lung ageing and disease
Birch, J., Barnes, P. J., & Passos, J. F. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.005 · Cited by 174
Non-homologous DNA end joining.
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Divide and conquer: nucleotide excision repair battles cancer and ageing
Mitchell, J. R., Hoeijmakers, J. H., & Niedernhofer, L. J. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00018-8 · Cited by 160
Spallarossa, P., Altieri, P., Aloi, C., Garibaldi, S., Barisione, C., Ghigliotti, G., Fugazza, G., Barsotti, A., & Brunelli, C. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00068.2009 · Cited by 170
Evidence that exposure of the telomere 3′ overhang sequence induces senescence
Li, G., Eller, M. S., Firoozabadi, R., & Gilchrest, B. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0235444100 · Cited by 155
Satyanarayana, A., Wiemann, S. U., Buer, J., Lauber, J., Dittmar, K. E. J., Wüstefeld, T., Blasco, M. A., Manns, M. P., & Rudolph, K. L. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg367 · Cited by 158
Regulation of growth arrest in senescence: Telomere damage is not the end of the story
Herbig, U., & Sedivy, J. M. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.09.002 · Cited by 163
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Extra-telomeric Functions of Human Telomerase: Cancer, Mitochondria and Oxidative Stress
Saretzki, G. C. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612820666140630095606 · Cited by 162
“Telomere uncapping and opening of the telomeric loop emanates DNA damage signals that could halt the cell cycle via p53 activation, and potentially result in either senescence or apoptosis [16, 17].”
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Vascular cell senescence and vascular aging
Minamino, T., Miyauchi, H., Yoshida, T., Tateno, K., Kunieda, T., & Komuro, I. (2003) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2003.11.010 · Cited by 153
“[52] Smogorzewska A, de Lange T.”
BackgroundCellular senescence and chromatin structure
Funayama, R., & Ishikawa, F. (2007) · Chromosoma · doi:10.1007/s00412-007-0115-7 · Cited by 153
Telomeres, interstitial telomeric repeat sequences, and chromosomal aberrations
Bolzán, A. D., & de Bianchi, M. S. A. (2006) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2005.12.003 · Cited by 151
Comparison between TRF2 and TRF1 of their telomeric DNA‐bound structures and DNA‐binding activities
Hanaoka, S., Nagadoi, A., & Nishimura, Y. (2004) · Protein Science · doi:10.1110/ps.04983705 · Cited by 157
Closed chromatin loops at the ends of chromosomes
Tv, N., & Woodcock, C. L. F. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403118 · Cited by 154
“Th e Jo ur na l o f C el l B io lo gy JCB © The Rockefeller University Press, 0021-9525/2004/07/161/5 $8.00 The Journal of Cell Biology, Volume 166, Number 2, July 19, 2004 161–165 http://www.jcb.org/cgi/doi/10.1083/jcb.200403118 161 Report Closed chromatin loops at the ends of chromosomes”
BackgroundInfluentialTelomeres and Telomerase in Aging, Regeneration and Cancer
Djojosubroto, M. W., Choi, Y. S., Lee, H., & Rudolph, K. L. (2003) · Molecules and Cells · doi:10.1016/s1016-8478(23)13723-x · Cited by 146
Munro, J., Barr, N. I., Ireland, H., Morrison, V., & Parkinson, E. K. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.01.017 · Cited by 141
Risques, R. A., Lai, L. A., Himmetoğlu, Ç., Ebaee, A., Li, L., Feng, Z., Bronner, M. P., Al-Lahham, B., Kowdley, K. V., Lindor, K. D., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-1966 · Cited by 145
Ink4a/Arf links senescence and aging
Sharpless, N. E. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2004.06.025 · Cited by 142
Ferreira, M. G., Miller, K. M., & Cooper, J. P. (2004) · Molecular Cell · doi:10.1016/s1097-2765(03)00531-8 · Cited by 142
Alternative end-joining mechanisms: a historical perspective
Decottignies, A. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00048 · Cited by 140
“Cells have evolved two main pathways to repair these lesions: the non-homologous end-joining (NHEJ) pathway, that ensures direct resealing of DNA ends; and the homologous recombination (HR) pathway that relies on the presence of homologous DNA sequences for DSB repair.”
BackgroundIncreased gene dosage of Ink4a/Arf results in cancer resistance and normal agingPreprint
Matheu, A., Pantoja, C., Efeyan, A., Criado, L. M., Martín‐Caballero, J., Flores, J. M., Klatt, P., & Serrano, M. (2004) · Genes & Development · doi:10.1101/gad.310304 · Cited by 140
“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).”
BackgroundClues to catastrophic telomere loss in mammals from yeast telomere rapid deletion
Lustig, A. J. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1207 · Cited by 138
“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”
BackgroundMartin-Ruiz, C. M., Saretzki, G. C., Petrie, J., Ladhoff, J., Jeyapalan, J. C., Wei, W., Sedivy, J. M., & von Zglinicki, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311980200 · Cited by 134
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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