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Science 29 March 2002:
Vol. 295. no. 5564, pp. 2446 - 2449
DOI: 10.1126/science.1069523
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Reports

Senescence Induced by Altered Telomere State, Not Telomere Loss

Jan Karlseder, Agata Smogorzewska, Titia de Lange*

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.

Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
*   To whom correspondence should be addressed. E-mail: delange{at}mail.rockefeller.edu

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Mol. Cell. Biol. 23, 6533-6541
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Inhibition of c-Myc Oncoprotein Limits the Growth of Human Melanoma Cells by Inducing Cellular Crisis.
A. Biroccio, S. Amodei, A. Antonelli, B. Benassi, and G. Zupi (2003)
J. Biol. Chem. 278, 35693-35701
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Telomerase Therapeutics: Telomeres Recognized as a DNA Damage Signal: Commentary re: K. Kraemer et al., Antisense-mediated hTERT inhibition specifically reduces the growth of human bladder cancer cells. Clin. Cancer Res., 9: 3794-3800, 2003..
J. W. Shay (2003)
Clin. Cancer Res. 9, 3521-3525
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A novel pseudoknot element is essential for the action of a yeast telomerase.
Y. Tzfati, Z. Knight, J. Roy, and E. H. Blackburn (2003)
Genes & Dev. 17, 1779-1788
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The Different Biological Effects of Telomestatin and TMPyP4 Can Be Attributed to Their Selectivity for Interaction with Intramolecular or Intermolecular G-Quadruplex Structures.
M.-Y. Kim, M. Gleason-Guzman, E. Izbicka, D. Nishioka, and L. H. Hurley (2003)
Cancer Res. 63, 3247-3256
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Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival.
K.-D. Wu, L. M. Orme, J. Shaughnessy Jr, J. Jacobson, B. Barlogie, and M. A. S. Moore (2003)
Blood 101, 4982-4989
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TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres.
W. Chang, J. N. Dynek, and S. Smith (2003)
Genes & Dev. 17, 1328-1333
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Role of Telomeres and Telomerase in the Pathogenesis of Human Cancer.
W. C. Hahn (2003)
J. Clin. Oncol. 21, 2034-2043
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Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process..
P. L. Opresko, W.-H. Cheng, C. von Kobbe, J. A. Harrigan, and V. A. Bohr (2003)
Carcinogenesis 24, 791-802
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Telomere Dynamics in Myelodysplastic Syndrome Determined by Telomere Measurement of Marrow Metaphases.
G. Sashida, J. H. Ohyashiki, A. Nakajima, M. Sumi, K. Kawakubo, T. Tauchi, and K. Ohyashiki (2003)
Clin. Cancer Res. 9, 1489-1496
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