CoChat
Sign Up
Cited by 293Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsDNA and Nucleic Acid Chemistry

Does a Sentinel or a Subset of Short Telomeres Determine Replicative Senescence?

Open access
Zou, Ying, Sfeir, Agnel, Gryaznov, Sergei M., Shay, Jerry W., Wright, Woodring E.·2004·Molecular Biology of the Cell
DOI 10.1091/mbc.e04-03-0207PMC PMC491830
Open this paper in CoChat — free account

Abstract

The proliferative life span of human cells is limited by telomere shortening, but the specific telomeres responsible for determining the onset of senescence have not been adequately determined. We here identify the shortest telomeres by the frequency of signal-free ends after in situ hybridization with telomeric probes and demonstrate that probes adjacent to the shortest ends colocalize with γH2AX-positive DNA damage foci in senescent cells. Normal BJ cells growth arrest at senescence before developing significant karyotypic abnormalities. We also identify all of the telomeres involved in end-associations in BJ fibroblasts whose cell-cycle arrest at the time of replicative senescence has been blocked and demonstrate that the 10% of the telomeres with the shortest ends are involved in >90% of all end-associations. The failure to find telomeric end-associations in near-senescent normal BJ metaphases, the presence of signal-free ends in 90% of near-senescent metaphases, and the colocalization of short telomeres with DNA damage foci in senescent interphase cells suggests that end-associations rather than damage signals from short telomeres per se may be the proximate cause of growth arrest. These results demonstrate that a specific group of chromosomes with the shortest telomeres rather than either all or only one or two sentinel telomeres is responsible for the induction of replicative senescence.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1091/mbc.e04-03-0207

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Extensive telomere uncapping may induce a stress response that does not occur when cells undergo telomere-dependent replicative senescence, which is thought to entail only a few dysfunctional telomeres.

    “Of course, extensive telomere uncapping may induce a stress response that does not occur when cells undergo telomere-dependent replicative senescence, which is thought to entail only a few dysfunctional telomeres (Zou et al., 2004).”

    From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Zou et al., 2004

    The study’s summary and discussion report that only a few short telomeres are involved in any given cell at senescence, supporting the second part of the sentence. The discussion considers DNA-damage signaling and telomere deprotection, but does not say that extensive uncapping may produce a distinct stress response absent from telomere-dependent replicative senescence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Loss of telomere function at a few chromosome ends is sufficient to induce replicative arrest.

    “Loss of telomere function at a few chromosome ends in a cell is sufficient to induce replicative arrest9,39,40 (FIG. 2b).”

    From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [40]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 45 · Cited by 293

Research works printed but not linked: 32

  1. Allshire, R.C., Dempster, M., and Hastie, N.D. (1989). Human telomeres contain at least three types of G-rich repeat distributed non-randomly. Nucleic Acids Res. 17, 4611-4627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atamna, H., Paler-Martinez, A., and Ames, B.N. (2000). N-t-butyl hydroxylamine, a hydrolysis product of alpha-phenyl-N-t-butyl nitrone, is more potent in delaying senescence in human lung fibroblasts. J. Biol. Chem. 275, 6741-6748. [DOI] [PubMed] [Google Scholar]
  3. Baird, D.M., Coleman, J., Rosser, Z.H., and Royle, N.J. (2000). High levels of sequence polymorphism and linkage disequilibrium at the telomere of 12q: implications for telomere biology and human evolution. Am. J. Hum. Genet. 66, 235-250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baird, D.M., Rowson, J., Wynford-Thomas, D., and Kipling, D. (2003). Extensive allelic variation and ultrashort telomeres in senescent human cells. Nat. Genet. 33, 203-207. [DOI] [PubMed] [Google Scholar]
  5. Barbosa, M.S., Vass, W.C., Lowy, D.R., and Schiller, J.T. (1991). In vitro biological activities of the E6 and E7 genes vary among human papillomaviruses of different oncogenic potential. J. Virol. 65, 292-298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Benn, P.A. (1976). Specific chromosome aberrations in senescent fibroblast cell lines derived from human embryos. Am. J. Hum. Genet. 28, 465-473. [PMC free article] [PubMed] [Google Scholar]
  7. Drayton, S., and Peters, G. (2002). Immortalisation and transformation revisited. Curr. Opin. Genet. Dev. 12, 98-104. [DOI] [PubMed] [Google Scholar]
  8. Dunham, M.A., Neumann, A.A., Fasching, C.L., and Reddel, R.R. (2000). Telomere maintenance by recombination in human cells. Nat. Genet. 26, 447-450. [DOI] [PubMed] [Google Scholar]
  9. Forsyth, N.R., Evans, A.P., Shay, J.W., and Wright, W.E. (2003). Developmental differences in the immortalization of lung fibroblasts by telomerase. Aging Cell 2, 235-243. [DOI] [PubMed] [Google Scholar]
  10. Graakjaer, J., Bischoff, C., Korsholm, L., Holstebroe, S., Vach, W., Bohr, V.A., Christensen, K., and Kolvraa, S. (2003). The pattern of chromosome-specific variations in telomere length in humans is determined by inherited, telomere-near factors and is maintained throughout life. Mech. Ageing Dev. 124, 629-640. [DOI] [PubMed] [Google Scholar]
  11. Greider, C.W. (1990). Telomeres, telomerase and senescence. Bioessays 12, 363-369. [DOI] [PubMed] [Google Scholar]
  12. Gustashaw, K.M. (1997). Chromsome Stains. Philadelphia: Lippincott-Raven.
  13. Halbert, C.L., Demers, G.W., and Galloway, D.A. (1992). The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells. J. Virol. 66, 2125-2134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hara, E., Tsurui, H., Shinozaki, A., Nakada, S., and Oda, K. (1991). Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1. Biochem. Biophys. Res. Commun. 179, 528-534. [DOI] [PubMed] [Google Scholar]
  15. Harley, C.B. (1991). Telomere loss: mitotic clock or genetic time bomb? Mutat. Res. 256, 271-282. [DOI] [PubMed] [Google Scholar]
  16. Hayflick, L., and Moorhead, P.S. (1961). The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585-621. [DOI] [PubMed] [Google Scholar]
  17. Levy, M.Z., Allsopp, R.C., Futcher, A.B., Greider, C.W., and Harley, C.B. (1992). Telomere end-replication problem and cell aging. J. Mol. Biol. 225, 951-960. [DOI] [PubMed] [Google Scholar]
  18. Lingner, J., Cooper, J.P., and Cech, T.R. (1995). Telomerase and DNA end replication: no longer a lagging strand problem? Science 269, 1533-1534. [DOI] [PubMed] [Google Scholar]
  19. Londono-Vallejo, J.A., DerSarkissian, H., Cazes, L., and Thomas, G. (2001). Differences in telomere length between homologous chromosomes in humans. Nucleic Acids Res. 29, 3164-3171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lorenz, M., Saretzki, G., Sitte, N., Metzkow, S., and von Zglinicki, T. (2001). BJ fibroblasts display high antioxidant capacity and slow telomere shortening independent of hTERT transfection. Free Radic. Biol. Med. 31, 824-831. [DOI] [PubMed] [Google Scholar]
  21. Masutomi, K. et al. (2003). Telomerase maintains telomere structure in normal human cells. Cell 114, 241-253. [DOI] [PubMed] [Google Scholar]
  22. Ouellette, M.M., Liao, M., Herbert, B.S., Johnson, M., Holt, S.E., Liss, H.S., Shay, J.W., and Wright, W.E. (2000). Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J. Biol. Chem. 275, 10072-10076. [DOI] [PubMed] [Google Scholar]
  23. Saksela, E., and Moorhead, P.S. (1963). Aneuploidy in the degenerative phase of serial cultivation of human cell strains. Proc. Natl. Acad. Sci. USA 50, 390-395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Scheffner, M., Werness, B.A., Huibregtse, J.M., Levine, A.J., and Howley, P.M. (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129-1136. [DOI] [PubMed] [Google Scholar]
  25. Shay, J.W., Pereira-Smith, O.M., and Wright, W.E. (1991). A role for both RB and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33-39. [DOI] [PubMed] [Google Scholar]
  26. Sherwood, S.W., Rush, D., Ellsworth, J.L., and Schimke, R.T. (1988). Defining cellular senescence in IMR-90 cells: a flow cytometric analysis. Proc. Natl. Acad. Sci. USA 85, 9086-9090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Steinert, S., Shay, J.W., and Wright, W.E. (2000). Transient expression of human telomerase extends the life span of normal human fibroblasts. Biochem. Biophys. Res. Commun. 273, 1095-1098. [DOI] [PubMed] [Google Scholar]
  28. Suda, T., Fujiyama, A., Takimoto, M., Igarashi, M., Kuroiwa, T., Waguri, N., Kawai, H., Mita, Y., and Aoyagi, Y. (2002). Interchromosomal telomere length variation. Biochem. Biophys. Res. Commun. 291, 210-214. [DOI] [PubMed] [Google Scholar]
  29. Takai, H., Smogorzewska, A., and de Lange, T. (2003). DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549-1556. [DOI] [PubMed] [Google Scholar]
  30. Thompson, K.V., and Holliday, R. (1975). Chromosome changes during the in vitro ageing of MRC-5 human fibroblasts. Exp. Cell Res. 96, 1-6. [DOI] [PubMed] [Google Scholar]
  31. Werness, B.A., Levine, A.J., and Howley, P.M. (1990). Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76-79. [DOI] [PubMed] [Google Scholar]
  32. Wright, W.E., and Shay, J.W. (2002). Historical claims and current interpretations of replicative aging. Nat. Biotechnol. 20, 682-688. [DOI] [PubMed] [Google Scholar]

Authors
Zou, Y., Sfeir, A., Gryaznov, S. M., Shay, J. W., & Wright, W. E.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Geron (United States) (US)
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2004-08
Volume
15
Issue
8
Pages
3709-3718
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e04-03-0207
PMC
PMC491830
OpenAlex
W2095696971
Cited by
293
References
45
Citations by year
2026: 5 · 2025: 5 · 2024: 9 · 2023: 5 · 2022: 16 · 2021: 18 · 2020: 18 · 2019: 16 · 2018: 10 · 2017: 12 · 2016: 15 · 2015: 11 · 2014: 9 · 2013: 10 · 2012: 12
FWCI
12.78
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG07992, R01AG007992)
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, DNA damage foci, γH2AX, cell cycle arrest, karyotype abnormalities, growth arrest
MeSH terms
Chromosomes, Human, DNA, DNA Damage, DNA Replication, Fibroblasts, Histones, Humans, Telomere, Cellular Senescence, In Situ Hybridization

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