Abstract
Maintenance of telomeres is essential for chromosome stability. In the absence of telomerase, telomeres shorten with cell division until they approach a stability threshold, at which point cells enter senescence. When senescence-signaling pathways are inactive, further telomere shortening leads to chromosome instability characterized by telomeric fusions and breakage-fusion-bridge (BFB) cycles. Since the distribution of telomere lengths among chromosome extremities is heterogeneous, we wondered about the impact of such variability on the stability of particular chromosome arms. We correlated the initial length of individual telomeres in telomerase-negative-transformed cells with the stability of the corresponding chromosome arms during the precrisis period. We show that arms carrying the shortest telomeres are the first to become unstable and this instability affects the chromosome homologues with shorter telomeres almost exclusively. The analysis of several postcrisis cell populations, which had stabilized their telomeres by re-expressing telomerase, showed that the karyotypic outcome is strongly influenced by the initial telomere length heterogeneity. The timing of telomerase re-expression also seems to play a role in limiting the extent of karyotypic changes, probably by reducing the frequency of telomeric fusions and hence BFB. Since the distribution of telomere lengths within somatic cells is proper to every individual, our results predict that the risk for a particular chromosome arm of becoming unstable early in tumorigenesis will differ between individuals and contribute directly to the heterogeneity of chromosome aberrations found in tumors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aisner DL, Wright WE and Shay JW . (2002). Curr. Opin. Genet. Dev., 12, 80–85.
Allsopp RC, Chang E, Kashefi-Aazam M, Rogaev EI, Piatyszek MA, Shay JW and Harley CB . (1995). Exp. Cell Res., 220, 194–200.
Allsopp RC and Harley CB . (1995). Exp. Cell Res., 219, 130–136.
Artandi SE and DePinho RA . (2000). Curr. Opin. Genet. Dev., 10, 39–46.
Baird DM, Rowson J, Wynford-Thomas D and Kipling D . (2003). Nat. Genet., 33, 203–207.
Blackburn EH . (2001). Cell, 106, 661–673.
Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, De Pinho RA and Greider CW . (1997). Cell, 91, 25–34.
Cherif D, Romana S, Der-Sarkissian H, Jones C and Berger R . (1993). Genes Chromosomes Cancer, 6, 107–112.
Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB and Bacchetti S . (1992). EMBO J., 11, 1921–1929.
Counter CM, Botelho FM, Wang P, Harley CB and Bacchetti S . (1994). J. Virol., 68, 3410–3414.
DePinho RA . (2000). Nature, 408, 248–254.
Der-Sarkissian H, Vergnaud G, Borde YM, Thomas G and Londono-Vallejo JA . (2002). Genome Res., 12, 1673–1678.
Ducray C, Pommier JP, Martins L, Boussin FD and Sabatier L . (1999). Oncogene, 18, 4211–4223.
Duncan EL and Reddel RR . (1997). Biochemistry (MOSC), 62, 1263–1274.
Gisselsson D . (2003). Adv. Cancer Res., 87, 1–29.
Gisselsson D, Jonson T, Petersen A, Strombeck B, Dal Cin P, Hoglund M, Mitelman F, Mertens F and Mandahl N . (2001). Proc. Natl. Acad. Sci. USA, 98, 12683–12688.
Gisselsson D, Pettersson L, Hoglund M, Heidenblad M, Gorunova L, Wiegant J, Mertens F, Dal Cin P, Mitelman F and Mandahl N . (2000). Proc. Natl. Acad. Sci. USA, 97, 5357–5362.
Graakjaer J, Bischoff C, Korsholm L, Holstebroe S, Vach W, Bohr VA, Christensen K and Kolvraa S . (2003). Mech. Ageing Dev., 124, 629–640.
Hackett JA, Feldser DM and Greider CW . (2001). Cell, 106, 275–286.
Hackett JA and Greider CW . (2002). Oncogene, 21, 619–626.
Halvorsen TL, Leibowitz G and Levine F . (1999). Mol. Cell. Biol., 19, 1864–1870.
Hande MP, Samper E, Lansdorp P and Blasco MA . (1999). J. Cell Biol., 144, 589–601.
Henderson S, Allsopp R, Spector D, Wang SS and Harley C . (1996). J. Cell Biol., 134, 1–12.
Ishikawa F . (1997). Biochem. Biophys. Res. Commun., 230, 1–6.
Karlseder J, Smogorzewska A and de Lange T . (2002). Science, 29, 2446–2449.
Lansdorp PM . (2000). Mech. Ageing Dev., 118, 23–34.
Lansdorp PM, Verwoerd NP, van de Rijke FM, Dragowska V, Little MT, Dirks RW, Raap AK and Tanke HJ . (1996). Hum. Mol. Genet., 5, 685–691.
Londono-Vallejo JA, DerSarkissian H, Cazes L and Thomas G . (2001). Nucleic Acids Res., 29, 3164–3171.
Martens UM, Zijlmans JM, Poon SS, Dragowska W, Yui J, Chavez EA, Ward RK and Lansdorp PM . (1998). Nat. Genet., 18, 76–80.
Stewart N and Bacchetti S . (1991). Virology, 180, 49–57.
Stewart SA, Ben-Porath I, Carey VJ, O'Connor BF, Hahn WC and Weinberg RA . (2003). Nat. Genet., 33, 492–496.
Zakian VA . (1995). Science, 270, 1601–1607.
Zijlmans JM, Martens UM, Poon SS, Raap AK, Tanke HJ, Ward RK and Lansdorp PM . (1997). Proc. Natl. Acad. Sci. USA, 94, 7423–7428.
Acknowledgements
We thank M D'Eletto for telomerase assays and G Vergnaud for some of the BAC/PAC clones used here. This work was supported by Grant ARC-4779 to JA L-V.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
der-Sarkissian, H., Bacchetti, S., Cazes, L. et al. The shortest telomeres drive karyotype evolution in transformed cells. Oncogene 23, 1221–1228 (2004). https://doi.org/10.1038/sj.onc.1207152
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207152
Keywords
This article is cited by
-
Feeders facilitate telomere maintenance and chromosomal stability of embryonic stem cells
Nature Communications (2018)
-
The methylation and telomere landscape in two families of marsupials with different rates of chromosome evolution
Chromosome Research (2018)
-
Association of telomere instability with senescence of porcine cells
BMC Cell Biology (2012)
-
Assessment of infection with polyomaviruses BKV, JCV and SV40 in different groups of Cuban individuals
Archives of Virology (2012)
-
Expression analysis of mitotic spindle checkpoint genes in breast carcinoma: role of NDC80/HEC1 in early breast tumorigenicity, and a two-gene signature for aneuploidy
Molecular Cancer (2011)