Senescence Induced by Altered Telomere State, Not Telomere Loss

Karlseder, Jan; Smogorzewska, Agata; de Lange, Titia

doi:10.1126/science.1069523

Cited by 797Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsDNA and Nucleic Acid Chemistry

Senescence Induced by Altered Telomere State, Not Telomere Loss

Karlseder, Jan, Smogorzewska, Agata, de Lange, Titia·2002·Science

DOI 10.1126/science.1069523

Open this paper in CoChat — free account

Abstract

Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.

Integrity signals

Registry

Crossref · 10.1126/science.1069523

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

TRF2-dependent suppression of DNA repair within telomeres can yield DDR signaling from telomere-associated damage resulting from causes other than telomere shortening.
“In addition, the TRF2-dependent suppression of DNA repair within telomeres can yield DDR signaling from telomere-associated damage resulting from causes other than telomere shortening (Karlseder et al. 2002; Fumagalli et al. 2012).”
From Cellular senescence and its effector programs (2014) · cites this paper as Karlseder et al. 2002
Overexpression of TRF2 can delay senescence, indicating that the DDR in senescence results from insufficient shelterin loading at shortened telomeres.
“Furthermore, over-expression of the shelterin subunit telomeric repeat-binding factor 2 (TRF2; also known as TERF2) can delay the onset of senescence44, arguing that the DDR in senescence is due to an insufficient loading of shelterin at the shortened telomeres.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [44]
TRF2 overexpression delays replicative senescence onset, indicating that TRF2 capacity to sequester the telomere terminus via the t-loop conformation might suppress the DNA damage signal from too short telomere ends and protect them from ATM signaling.
“In agreement, TRF2 overexpression delays replicative senescence onset [101], indicating that TRF2 capacity to sequester the telomere terminus via the t-loop conformation [88] might suppress the DNA damage signal from too short telomere ends and protect them from ATM signaling.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [101]

Telomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750 · see citing works
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., & Wright, W. E. (1998) · Science · doi:10.1126/science.279.5349.349 · Cited by 4,975 · see citing works
Mammalian Telomeres End in a Large Duplex Loop
Griffith, J. D., Comeau, L., Rosenfield, S., Stansel, R. M., Bianchi, A., Moss, H., & de Lange, T. (1999) · Cell · doi:10.1016/s0092-8674(00)80760-6 · Cited by 2,447 · see citing works
Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.
Counter, C. M., Avilion, A. A., LeFeuvre, C. E., Stewart, N. G., Greider, C. W., Harley, C. B., & Bacchetti, S. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05245.x · Cited by 2,096 · see citing works
Untitled work
Olovnikov (1973) · doi:10.1016/0022-5193(73)90198-7 · Cited by 1,847 · see citing works
TRF2 Protects Human Telomeres from End-to-End Fusions
van Steensel, B., Smogorzewska, A., & de Lange, T. (1998) · Cell · doi:10.1016/s0092-8674(00)80932-0 · Cited by 1,709 · see citing works
Self-citation
Origin of Concatemeric T7DNA
WATSON, J. D. (1972) · Nature New Biology · doi:10.1038/newbio239197a0 · Cited by 1,632 · see citing works
Control of telomere length by the human telomeric protein TRF1
van Steensel, B., & de Lange, T. (1997) · Nature · doi:10.1038/385740a0 · Cited by 1,219 · see citing works
p53- and ATM-Dependent Apoptosis Induced by Telomeres Lacking TRF2
Karlseder, J., Broccoli, D., Dai, Y., Hardy, S., & de Lange, T. (1999) · Science · doi:10.1126/science.283.5406.1321 · Cited by 1,086 · see citing works
Self-citation
Protection of mammalian telomeres
de Lange, T. (2002) · Oncogene · doi:10.1038/sj.onc.1205080 · Cited by 942 · see citing works
Human telomeres contain two distinct Myb–related proteins, TRF1 and TRF2
Broccoli, D., Smogorzewska, A., Chong, L., & de Lange, T. (1997) · Nature Genetics · doi:10.1038/ng1097-231 · Cited by 926 · see citing works
Self-citation
Long G Tails at Both Ends of Human Chromosomes Suggest a C Strand Degradation Mechanism for Telomere Shortening
Makarov, V. L., Hirose, Y., & Langmore, J. P. (1997) · Cell · doi:10.1016/s0092-8674(00)81908-x · Cited by 923 · see citing works
A mutant with a defect in telomere elongation leads to senescence in yeast
Lundblad, V., & Szostak, J. W. (1989) · Cell · doi:10.1016/0092-8674(89)90132-3 · Cited by 909 · see citing works
Control of Human Telomere Length by TRF1 and TRF2
Smogorzewska, A., van Steensel, B., Bianchi, A., Oelmann, S., Schaefer, M. R., Schnapp, G., & de Lange, T. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.5.1659-1668.2000 · Cited by 768 · see citing works
Self-citation
Hayflick, his limit, and cellular ageing
Shay, J. W., & Wright, W. E. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35036093 · Cited by 764 · see citing works
A role for both RB and p53 in the regulation of human cellular senescence*1
SHAY, J. (1991) · Experimental Cell Research · doi:10.1016/0014-4827(91)90453-2 · Cited by 757 · see citing works
TLC1 : Template RNA Component of Saccharomyces cerevisiae Telomerase
Singer, M. S., & Gottschling, D. E. (1994) · Science · doi:10.1126/science.7545955 · Cited by 736 · see citing works
Sugar and Disease
Yudkin, J. S. (1972) · Nature · doi:10.1038/239197a0 · Cited by 543 · see citing works
Telomere Shortening Is Associated with Cell Division in Vitro and in Vivo
Allsopp, R. C., Chang, E., Kashefi-Aazam, M., Rogaev, E. I., Piatyszek, M. A., Shay, J. W., & Harley, C. B. (1995) · Experimental Cell Research · doi:10.1006/excr.1995.1306 · Cited by 533 · see citing works
T‐loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang
Stansel, R. M., de Lange, T., & Griffith, J. D. (2001) · The EMBO Journal · doi:10.1093/emboj/20.19.5532 · Cited by 529 · see citing works
Telomeric localization of TRF2, a novel human telobox protein
Bilaud, T., Brun, C., Ancelin, K., Koering, C., Laroche, T., & Gilson, É. (1997) · Nature Genetics · doi:10.1038/ng1097-236 · Cited by 506 · see citing works
Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells: a comparison of the "hot spot" mutant phenotypes.
Hinds, P. W., Finlay, C. A., Quartin, R. S., Baker, S. J., Fearon, E. R., Vogelstein, B., & Levine, A. J. (1990) · PubMed · Cited by 408 · see citing works
Telomere Shortening Is Proportional to the Size of the G-rich Telomeric 3′-Overhang
Huffman, K. E., Levene, S. D., Tesmer, V. M., Shay, J. W., & Wright, W. E. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002843200 · Cited by 274 · see citing works
Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1
Hara, E., Tsurui, H., Shinozaki, A., Nakada, S., & Oda, K. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(91)91403-y · Cited by 260 · see citing works
African Butterflies
WATSON, A. (1972) · Nature · doi:10.1038/239056a0 · Cited by 33 · see citing works

Flagged first, then by citations

Sorted by citations

DNA Damage Foci at Dysfunctional Telomeres
Takai, H., Smogorzewska, A., & de Lange, T. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00542-6 · Cited by 1,409 · see citing works
Self-citation
Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1
Treiner, E., Duban, L., Bahram, S., Radosavljevic, M., Wanner, V., Tilloy, F., Affaticati, P., Gilfillan, S., & Lantz, O. (2003) · Nature · doi:10.1038/nature01433 · Cited by 1,139 · see citing works
The signals and pathways activating cellular senescence
Ben-Porath, I., & Weinberg, R. A. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.10.013 · Cited by 1,046 · see citing works
Telomeres: protecting chromosomes against genome instability
O’Sullivan, R. J., & Karlseder, J. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2848 · Cited by 994 · see citing works
Self-citation
Untitled work
Wang (2012) · doi:10.1161/circresaha.111.261388 · Cited by 957 · see citing works
Human Telomerase and Its Regulation
Cong, Y.-S., Wright, W. E., & Shay, J. W. (2002) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.66.3.407-425.2002 · Cited by 898 · see citing works
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
Regulation of telomerase by telomeric proteins.
Smogorzewska, A., & de Lange, T. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.071403.160049 · Cited by 857 · see citing works
Self-citation
Telomeres in cancer: tumour suppression and genome instability
Maciejowski, J., & de Lange, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.171 · Cited by 745 · see citing works
Telomerase maintains telomere structure in normal human cells
Kenichi, M., Yu, E. Y., Shilagardi, K., Ben‐Porath, I., Currier, J. L., Metz, G. B., Brooks, M. W., Kaneko, S., Seishi, M., DeCaprio, J. A., et al. (2006) · Kanazawa University Repository for Academic Resources (DSpace) (Kanazawa University) · Cited by 738 · see citing works
Telomerase and cancer therapeutics
Harley, C. B. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2275 · Cited by 728 · see citing works
POT1 as a terminal transducer of TRF1 telomere length control
Loayza, D., & de Lange, T. (2003) · Nature · doi:10.1038/nature01688 · Cited by 696 · see citing works
DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion
Celli, G. B., & de Lange, T. (2005) · Nature Cell Biology · doi:10.1038/ncb1275 · Cited by 623 · see citing works
Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis
Grootaert, M. O. J., Moulis, M., Roth, L., Martinet, W., Vindis, C., Bennett, M. R., & De Meyer, G. R. Y. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy007 · Cited by 606 · see citing works
Telomeres and telomerase
Chan, S. R. W. L., & Blackburn, E. H. (2004) · Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences · doi:10.1098/rstb.2003.1370 · Cited by 595 · see citing works
53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility
Dimitrova, N., Chen, Y.-C. M., Spector, D. L., & de Lange, T. (2008) · Nature · doi:10.1038/nature07433 · Cited by 572 · see citing works
Extensive allelic variation and ultrashort telomeres in senescent human cells
Baird, D. M., Rowson, J., Wynford-Thomas, D., & Kipling, D. (2003) · Nature Genetics · doi:10.1038/ng1084 · Cited by 570 · see citing works
Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres
Wang, R. C., Smogorzewska, A., & de Lange, T. (2004) · Cell · doi:10.1016/j.cell.2004.10.011 · Cited by 507 · see citing works
Self-citation
Chronic Oxidative Stress Compromises Telomere Integrity and Accelerates the Onset of Senescence in Human Endothelial Cells
Kurz, D. J., Decary, S., Hong, Y., Trivier, E., Akhmedov, A., & Erusalimsky, J. D. (2004) · Journal of Cell Science · doi:10.1242/jcs.01097 · Cited by 499 · see citing works
Hallmarks of senescence in carcinogenesis and cancer therapy
Shay, J. W., & Roninson, I. B. (2004) · Oncogene · doi:10.1038/sj.onc.1207518 · Cited by 502 · see citing works
Different telomere damage signaling pathways in human and mouse cells
Smogorzewska, A., & de Lange, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf433 · Cited by 482 · see citing works
Self-citation
Replication and protection of telomeres
Verdun, R. E., & Karlseder, J. (2007) · Nature · doi:10.1038/nature05976 · Cited by 463 · see citing works
Self-citation
POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex
Ye, J. Z.-S., Hockemeyer, D., Krutchinsky, A. N., Loayza, D., Hooper, S. M., Chait, B. T., & de Lange, T. (2004) · Genes & Development · doi:10.1101/gad.1215404 · Cited by 459 · see citing works
The structure of telomeric DNA
Neidle, S., & Parkinson, G. N. (2003) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(03)00072-1 · Cited by 450 · see citing works
mTOR as a central regulator of lifespan and aging
Papadopoli, D. J., Boulay, K., Kazak, L., Pollak, M., Mallette, F. A., Topisirović, I., & Hulea, L. (2019) · F1000Research · doi:10.12688/f1000research.17196.1 · Cited by 431 · see citing works
Autophagic cell death restricts chromosomal instability during replicative crisis
Nassour, J., Radford, R., Correia, A., Fusté, J. M., Schoell, B., Jauch, A., Shaw, R. J., & Karlseder, J. (2019) · Nature · doi:10.1038/s41586-019-0885-0 · Cited by 429 · see citing works
Self-citation
Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1
Itahana, K., Zou, Y., Itahana, Y., Martinez, J.-L., Beausejour, C., Jacobs, J. J. L., van Lohuizen, M., Band, V., Campisi, J., & Dimri, G. P. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.389-401.2003 · Cited by 438 · see citing works
Beginning to Understand the End of the Chromosome
Cech, T. R. (2004) · Cell · doi:10.1016/s0092-8674(04)00038-8 · Cited by 417 · see citing works
Telosome, a Mammalian Telomere-associated Complex Formed by Multiple Telomeric Proteins
Liu, D., O'Connor, M. S., Qin, J., & Songyang, Z. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409293200 · Cited by 405 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
The Telomeric Protein TRF2 Binds the ATM Kinase and Can Inhibit the ATM-Dependent DNA Damage Response
Karlseder, J., Hoke, K., Mirzoeva, O. K., Bakkenist, C. J., Kastan, M. B., Petrini, J. H. J., & de Lange, T. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020240 · Cited by 393 · see citing works
Self-citation
Mitogen‐activated protein kinase p38 defines the common senescence‐signalling pathway
Iwasa, H., Han, J., & Ishikawa, F. (2003) · Genes to Cells · doi:10.1046/j.1365-2443.2003.00620.x · Cited by 388 · see citing works
ERCC1/XPF Removes the 3′ Overhang from Uncapped Telomeres and Represses Formation of Telomeric DNA-Containing Double Minute Chromosomes
Zhu, X., Niedernhofer, L. J., Küster, B., Mann, M., Hoeijmakers, J. H. J., & de Lange, T. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00478-7 · Cited by 382 · see citing works
Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer
Di Micco, R., Sulli, G., Dobreva, M., Liontos, M., Botrugno, O. A., Gargiulo, G., dal Zuffo, R., Matti, V., d'Ario, G., Montani, E., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2170 · Cited by 382 · see citing works
DNA Ligase IV-Dependent NHEJ of Deprotected Mammalian Telomeres in G1 and G2
Smogorzewska, A., Karlseder, J., Holtgreve-Grez, H., Jauch, A. S., & de Lange, T. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01179-x · Cited by 377 · see citing works
Self-citation
Ex vivo enrichment of mesenchymal cell progenitors by fibroblast growth factor 2
Bianchi, G., Banfi, A., Mastrogiacomo, M., Notaro, R., Luzzatto, L., Cancedda, R., & Quarto, R. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(03)00138-1 · Cited by 374 · see citing works
The roles of senescence and telomere shortening in cardiovascular disease
Fyhrquist, F., Saijonmaa, O. J., & Strandberg, T. E. (2013) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2013.30 · Cited by 368 · see citing works
When cells get stressed: an integrative view of cellular senescence
Ben-Porath, I., & Weinberg, R. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420663 · Cited by 404 · see citing works
Vascular Smooth Muscle Cell Senescence Promotes Atherosclerosis and Features of Plaque Vulnerability
Wang, J., Uryga, A. K., Reinhold, J., Figg, N., Baker, L., Finigan, A., Gray, K., Kumar, S., Clarke, M., & Bennett, M. (2015) · Circulation · doi:10.1161/circulationaha.115.016457 · Cited by 349 · see citing works
TIN2 Binds TRF1 and TRF2 Simultaneously and Stabilizes the TRF2 Complex on Telomeres
Ye, J. Z.-S., Donigian, J. R., van Overbeek, M., Loayza, D., Luo, Y., Krutchinsky, A. N., Chait, B. T., & de Lange, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409047200 · Cited by 346 · see citing works
Telomeres: Cancer to Human Aging
Stewart, S. A., & Weinberg, R. A. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.22.010305.104518 · Cited by 336 · see citing works
Erosion of the telomeric single-strand overhang at replicative senescence
Stewart, S. A., Ben-Porath, I., Carey, V. J., O'Connor, B. F., Hahn, W. C., & Weinberg, R. A. (2003) · Nature Genetics · doi:10.1038/ng1127 · Cited by 335 · see citing works
Structural Insights into G-Quadruplexes: Towards New Anticancer Drugs
Yang, D., & Okamoto, K. (2010) · Future Medicinal Chemistry · doi:10.4155/fmc.09.172 · Cited by 323 · see citing works
Telomere length homeostasis requires that telomerase levels are limiting
Cristofari, G., & Lingner, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7600952 · Cited by 315 · see citing works
DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?
Passos, J. F., Saretzki, G., & von Zglinicki, T. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm893 · Cited by 344 · see citing works
The Werner Syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2
Opresko, P. L., Otterlei, M., Graakjær, J., Bruheim, P., Dawut, L., Kølvraa, S., May, A., Seidman, M. M., & Bohr, V. A. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.05.023 · Cited by 305 · see citing works
A Dynamic Molecular Link between the Telomere Length Regulator TRF1 and the Chromosome End Protector TRF2
Houghtaling, B. R., Cuttonaro, L., Chang, W., & Smith, S. H. (2004) · Current Biology · doi:10.1016/j.cub.2004.08.052 · Cited by 284 · see citing works
Cellular Senescence in Neurodegenerative Diseases
Martínez-Cué, C., & Rueda, N. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00016 · Cited by 258 · see citing works
The p16INK4a-RB pathway : molecular link between cellular senescence and tumor suppression
Ohtani, N., Yamakoshi, K., Takahashi, A., & Hara, E. (2004) · The Journal of Medical Investigation · doi:10.2152/jmi.51.146 · Cited by 276 · see citing works
Functional links between telomeres and proteins of the DNA-damage response
d'Adda di Fagagna, F., Teo, S.-H., & Jackson, S. P. (2004) · Genes & Development · doi:10.1101/gad.1214504 · Cited by 277 · see citing works
Replicative senescence: a critical review
Cristofalo, V. J., Lorenzini, A., Allen, R. G., Torres, C. A., & Tresini, M. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.07.010 · Cited by 275 · see citing works
Telomere biology in healthy aging and disease
Oeseburg, H., de Boer, R. A., van Gilst, W. H., & van der Harst, P. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0728-1 · Cited by 273 · see citing works
Adriamycin-induced Senescence in Breast Tumor Cells Involves Functional p53 and Telomere Dysfunction
Elmore, L. W., Rehder, C. W., Di, X. M., McChesney, P. A., Jackson‐Cook, C. K., Gewirtz, D. A., & Holt, S. E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205477200 · Cited by 271 · see citing works
Regulation of the human catalytic subunit of telomerase (hTERT)
Daniel, M. G., Peek, G. W., & Tollefsbol, T. O. (2012) · Gene · doi:10.1016/j.gene.2012.01.095 · Cited by 265 · see citing works
Telomere shortening and survival in free-living corvids
Salomons, H. M., Mulder, G. A., van de Zande, L., Haussmann, M. F., Linskens, M. H. K., & Verhulst, S. (2009) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2009.0517 · Cited by 257 · see citing works
Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics – current status and future prospects
Kèlland, L. R. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2004.11.024 · Cited by 253 · see citing works
Telomere-Driven Tetraploidization Occurs in Human Cells Undergoing Crisis and Promotes Transformation of Mouse Cells
Davoli, T., & de Lange, T. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.044 · Cited by 242 · see citing works
Telomere dysfunction as a cause of genomic instability in Werner syndrome
Crabbe, L., Jauch, A., Naeger, C. M., Holtgreve-Grez, H., & Karlseder, J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609410104 · Cited by 240 · see citing works
Self-citation
Telomere loss in relation to age and early environment in long-lived birds
Hall, M. E., Nasir, L., Daunt, F., Gault, E. A., Croxall, J. P., Wanless, S., & Monaghan, P. (2004) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2004.2768 · Cited by 247 · see citing works
In Vivo Stoichiometry of Shelterin Components
Takai, K., Hooper, S., Blackwood, S., Gandhi, R., & de Lange, T. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.038026 · Cited by 243 · see citing works
Basic Biology of Oxidative Stress and the Cardiovascular System
Sack, M. N., Fyhrquist, F., Saijonmaa, O. J., Fuster, V., & Kovacic, J. C. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.05.034 · Cited by 243 · see citing works
Five dysfunctional telomeres predict onset of senescence in human cells
Kaul, Z., Cesare, A. J., Huschtscha, L. I., Neumann, A. A., & Reddel, R. R. (2012) · The EMBO Reports · doi:10.1038/embor.2011.227 · Cited by 225 · see citing works
“This supports previous conclusions that telomere structure, rather than telomere length per se , regulates senescence induction (Karlseder et al , 2002).”
Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-Binding Factor TRF2 in Endothelial Progenitor Cells
Spyridopoulos, I., Haendeler, J., Urbich, C., Brümmendorf, T. H., Oh, H., Schneider, M. D., Zeiher, A. M., & Dimmeler, S. (2004) · Circulation · doi:10.1161/01.cir.0000142866.50300.eb · Cited by 230 · see citing works
Telomere Protection by TPP1/POT1 Requires Tethering to TIN2
Takai, K., Kibe, T., Donigian, J. R., Frescas, D., & de Lange, T. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.043 · Cited by 229 · see citing works
Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia
Tauchi, T., Shin‐ya, K., Sashida, G., Sumi, M., Okabe, S., Ohyashiki, J. H., & Ohyashiki, K. (2006) · Oncogene · doi:10.1038/sj.onc.1209577 · Cited by 218 · see citing works
TIN2 Mediates Functions of TRF2 at Human Telomeres
Kim, S., Beausejour, C. M., Davalos, A. R., Kaminker, P. G., Heo, S., & Campisi, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408650200 · Cited by 212 · see citing works
Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci
Zhang, H., Pan, K.-H., & Cohen, S. N. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2627983100 · Cited by 209 · see citing works
Telomestatin-induced Telomere Uncapping Is Modulated by POT1 through G-overhang Extension in HT1080 Human Tumor Cells
Gómez, D., Wenner, T., Brassart, B., Douarre, C., O’Donohue, M.-F., El‐Khoury, V., Shin‐ya, K., Morjani, H., Trentesaux, C., & Riou, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605828200 · Cited by 207 · see citing works
Trisubstituted Acridines as G-quadruplex Telomere Targeting Agents. Effects of Extensions of the 3,6- and 9-Side Chains on Quadruplex Binding, Telomerase Activity, and Cell Proliferation
Moore, M. M., Schultes, C. M., Cuesta, J., Cuenca, F., Gunaratnam, M., Tanious, F. A., Wilson, W. D., & Neidle, S. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050555a · Cited by 205 · see citing works
The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures.
Kim, M.-Y., Gleason-Guzman, M. C., Izbicka, E., Nishioka, D., & Hurley, L. H. (2003) · PubMed · Cited by 205 · see citing works
DNA damage checkpoint kinase Chk2 triggers replicative senescence
Gire, V., Roux, P., Wynford‐Thomas, D., Brondello, J., & Dulic, V. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600259 · Cited by 198 · see citing works
TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeresPreprint
Chang, W., Dynek, J. N., & Smith, S. H. (2003) · Genes & Development · doi:10.1101/gad.1077103 · Cited by 200 · see citing works
Apollo, an Artemis-Related Nuclease, Interacts with TRF2 and Protects Human Telomeres in S Phase
van Overbeek, M., & de Lange, T. (2006) · Current Biology · doi:10.1016/j.cub.2006.05.022 · Cited by 195 · see citing works
Telomeres and Telomerase in Cardiovascular Diseases
Yeh, J., & Wang, C. (2016) · Genes · doi:10.3390/genes7090058 · Cited by 203 · see citing works
Telomeric Strategies: Means to an End
Jain, D., & Cooper, J. P. (2010) · Annual Review of Genetics · doi:10.1146/annurev-genet-102108-134841 · Cited by 196 · see citing works
Characterization of Oxidative Guanine Damage and Repair in Mammalian Telomeres
Wang, Z., Rhee, D. B., Lü, J., Bohr, C. T., Fang, Z., Vallabhaneni, H., de Souza-Pinto, N. C., & Liu, Y. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000951 · Cited by 192 · see citing works
The role of stem cells in aging
Zant, G. E. V., & Liang, Y. (2003) · Experimental Hematology · doi:10.1016/s0301-472x(03)00088-2 · Cited by 194 · see citing works
Activated p53 suppresses the histone methyltransferase EZH2 gene
Tang, X., Milyavsky, M., Shats, I., Erez, N., Goldfinger, N., & Rotter, V. (2004) · Oncogene · doi:10.1038/sj.onc.1207706 · Cited by 191 · see citing works
Influences on the reduction of relative telomere length over 10 years in the population-based Bruneck Study: introduction of a well-controlled high-throughput assay
Ehrlenbach, S., Willeit, P., Kiechl, S. J., Willeit, J., Reindl, M., Schanda, K., Kronenberg, F., & Kloss‐Brandstätter, A. (2009) · International Journal of Epidemiology · doi:10.1093/ije/dyp273 · Cited by 192 · see citing works
Alternative lengthening of telomeres, telomerase, and cancer
Reddel, R. R. (2003) · Cancer Letters · doi:10.1016/s0304-3835(02)00702-4 · Cited by 191 · see citing works
Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process.
Opresko, P. L. (2003) · Carcinogenesis · doi:10.1093/carcin/bgg034 · Cited by 187 · see citing works
The Human Rap1 Protein Complex and Modulation of Telomere Length
O’Connor, M. S., Safari, A., Liu, D., Qin, J., & Songyang, Z. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312913200 · Cited by 181 · see citing works
Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence
Benson, E. K., Lee, S. W., & Aaronson, S. A. (2010) · Journal of Cell Science · doi:10.1242/jcs.067306 · Cited by 185 · see citing works
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 180 · see citing works
Why are parasite contingency genes often associated with telomeres?
Barry, J. D., Ginger, M. L., Burton, P., & McCulloch, R. (2003) · International Journal for Parasitology · doi:10.1016/s0020-7519(02)00247-3 · Cited by 181 · see citing works
Regulation of Telomere Length by G-Quadruplex Telomere DNA- and TERRA-Binding Protein TLS/FUS
Takahama, K., Takada, A., Tada, S., Shimizu, M., Sayama, K., Kurokawa, R., & Oyoshi, T. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.02.013 · Cited by 183 · see citing works
Targeted 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 176 · see citing works
Self-citation
Aerobic fitness is associated with lower proportions of senescent blood T-cells in man
Spielmann, G., McFarlin, B. K., O’Connor, D. P., Smith, P. J. W., Pircher, H., & Simpson, R. J. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.07.226 · Cited by 180 · see citing works
Telomeres and chromosome instability
Murnane, J. P. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.05.030 · Cited by 174 · see citing works
A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection
Deng, Z., Wang, Z., Stong, N., Plasschaert, R. N., Moczan, A., Chen, H.-S., Hu, S., Wickramasinghe, P., Davuluri, R. V., Bartolomei, M. S., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.266 · Cited by 174 · see citing works
Telomerase beyond telomeres
Blasco, M. A. (2002) · Nature Reviews Cancer · doi:10.1038/nrc862 · Cited by 175 · see citing works
Rap1 Affects the Length and Heterogeneity of Human Telomeres
Li, B., & de Lange, T. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-06-0403 · Cited by 172 · see citing works
Senescence Regulation by the p53 Protein Family
Qian, Y., & Chen, X. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-239-1_3 · Cited by 170 · see citing works
The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability
Bettin, N., Pegorar, C. O., & Cusanelli, E. (2019) · Cells · doi:10.3390/cells8030246 · Cited by 167 · see citing works
The emerging role of alternative splicing in senescence and aging
Deschênes, M., & Chabot, B. (2017) · Aging Cell · doi:10.1111/acel.12646 · Cited by 167 · see citing works
The Telomere Deprotection Response Is Functionally Distinct from the Genomic DNA Damage Response
Cesare, A. J., Hayashi, M. T., Crabbe, L., & Karlseder, J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.06.006 · Cited by 155 · see citing works
Self-citation
A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest
Hayashi, M., Cesare, A. J., Fitzpatrick, J. A. J., Denchi, E. L., & Karlseder, J. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2245 · Cited by 166 · see citing works
Self-citation
Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival
Kang, M., Kim, R., Kim, S., Yip, F., Shin, K., Dimri, G. P., Christensen, R., Han, T., & Park, N. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603529 · Cited by 163 · see citing works
The Role of Telomere Biology in Cancer
Xu, L., Li, S., & Stohr, B. A. (2013) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-164030 · Cited by 160 · see citing works
Non-homologous DNA end joining.
Pastwa, E., & Błasiak, J. (2003) · Acta Biochimica Polonica · doi:10.18388/abp.2003_3622 · Cited by 163 · see citing works

Authors: Karlseder, J., Smogorzewska, A., & de Lange, T.
Affiliations: Rockefeller University (US)
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
ORCID: Karlseder, Jan
Smogorzewska, Agata
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2002-03-29
Volume: 295
Issue: 5564
Pages: 2446-2449
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1069523
OpenAlex: W2088926897
Cited by: 796
References: 25
Citations by year: 2026: 10 · 2025: 11 · 2024: 22 · 2023: 11 · 2022: 14 · 2021: 22 · 2020: 18 · 2019: 19 · 2018: 26 · 2017: 22 · 2016: 20 · 2015: 29 · 2014: 24 · 2013: 22 · 2012: 35
FWCI: 47.76
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (AG 16643)
National Cancer Institute (R01CA076027, CA76027)
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 and Nucleic Acid Chemistry
Keywords: replicative senescence, telomere shortening, TRF2, telomere length, telomere fusion, primary human cells, growth arrest
MeSH terms: Antigens, Polyomavirus Transforming, Cell Division, Cell Line, Cells, Cultured, DNA, DNA-Binding Proteins, Humans, Oncogene Proteins, Viral, Repressor Proteins, Retroviridae, Transformation, Genetic, Tumor Suppressor Protein p53, Retinoblastoma Protein, Telomere, Cellular Senescence, Telomeric Repeat Binding Protein 2, Papillomavirus E7 Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Senescence Induced by Altered Telomere State, Not Telomere Loss

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks