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Vol. 122, No. 3-4, 2008
Issue release date: February 2009

The number of dysfunctional telomeres in a cell: one amplifies; more than one translocate

Tusell L. · Soler D. · Agostini M. · Pampalona J. · Genescà A.
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Chromosomal instability is increasingly appreciated as a key component of tumorigenesis in humans. A combination of abnormal telomere shortening and cell-cycle checkpoint deficiency has been proposed as the initial lesions causing destabilizing chromatin bridges in proliferative cells. We examined the participation of the different types of end-to-end fusions in generating instable karyotypes in non-transformed human breast epithelial cells. We concluded that short dysfunctional telomeres represent an initiating substrate for post-replicative rejoining of sister chromatids and are likely to make an important contribution to the formation of chromosomal rearrangements and the amplification of chromosome arm segments in breast epithelial cells. We propose that there is a chronological order in the participation of the different types of end-to-end fusions in the generation of chromosomal instability. Thus, intrachromosomal post-replicative joining would proceed mainly in the early stages after overcoming growth arrest, when telomere dysfunction is limited and affects only one chromosome end in a cell. The absence of a second substrate for end joining will conduct the cell with the uncapped chromosome to replicate its DNA and fuse the uncapped sister chromatids after replication. Later, since telomeres shorten progressively with each DNA replication round, the uncapping will affect many more chromosome ends, and fusions between the uncapped ends from different chromosomes will be produced. While the fusion of sister chromatids will produce chromosome segment amplification and terminal deletions in the daughter cells, interchromosomal fusion will produce unbalanced rearrangements other than chromosome segment amplifications.

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  1. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, et al: Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406:641–645 (2000).
  2. Bignell GR, Santarius T, Pole JC, Butler AP, Perry J, et al: Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res 17:1296–1303 (2007).
  3. Brison O: Gene amplification and tumor progression. Biochim Biophys Acta 1155:25–41 (1993).
  4. Chin K, de Solorzano CO, Knowles D, Jones A, Chou W, et al: In situ analyses of genome instability in breast cancer. Nat Genet 36:984–988 (2004).
  5. Coelho PA, Queiroz-Machado J, Sunkel CE: Condensin-dependent localisation of topoisomerase II to an axial chromosomal structure is required for sister chromatid resolution during mitosis. J Cell Sci 116:4763–4776 (2003).
  6. Coquelle A, Toledo F, Stern S, Bieth A, Debatisse MA: New role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Mol Cell 2:259–265 (1998).
  7. Crabbe L, Karlseder J: In the end, it’s all structure. Curr Mol Med 5:135–143 (2005).
  8. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, et al: A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198 (2003).
  9. de Lange T: Protection of mammalian telomeres. Oncogene 21:532–540 (2002).
  10. DePinho RA: The age of cancer. Nature 408:248–254 (2000).
  11. der-Sarkissian H, Bacchetti S, Cazes L, Londoño-Vallejo JA: The shortest telomeres drive karyotype evolution in transformed cells. Oncogene 23:1221–1228 (2004).
  12. Espejel S, Franco S, Rodríguez-Perales S, Bouffler SD, Cigudosa JC, Blasco MA: Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J 21:2207–2219 (2002).
  13. Gisselsson D: Mitotic instability in cancer: is there method in the madness? Cell Cycle 4:1007–1010 (2005).
  14. Gisselsson D, Höglund M: Connecting mitotic instability and chromosome aberrations in cancer–can telomeres bridge the gap? Semin Cancer Biol 15:13–23 (2005).
  15. Gisselsson D, Pettersson L, Höglund M, Heidenblad M, Gorunova L, et al: Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci USA 97:5357–5362 (2000).
  16. Gisselsson D, Jonson T, Petersén A, Strömbeck B, Dal Cin P, et al: Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci USA 98:12683–12688 (2001).
  17. Glover TW, Arlt MF, Casper AM, Durkin SG: Mechanisms of common fragile site instability. Hum Mol Genet 14:R197–205 (2005).
  18. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, et al: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880 (2001).
  19. Graakjaer J, Pascoe L, Der-Sarkissian H, Thomas G, Kolvraa S, et al: The relative lengths of individual telomeres are defined in the zygote and strictly maintained during life. Aging Cell 3:97–102 (2004).
  20. Hackett JA, Feldser DM, Greider CW: Telomere dysfunction increases mutation rate and genomic instability. Cell 106:275–286 (2001).
  21. Haering CH, Nasmyth K: Building and breaking bridges between sister chromatids. Bioessays 25:1178–1191 (2003).
  22. Hemann MT, Strong MA, Hao LY, Greider CW: The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107:67–77 (2001).
  23. Holst CR, Nuovo GJ, Esteller M, Chew K, Baylin SB, et al: Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res 63:1596–1601 (2003).
  24. Jallepalli PV, Lengauer C: Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer 1:109–117 (2001).
  25. Lansdorp PM, Verwoerd NP, van de Rijke FM, Dragowska V, Little MT, et al: Heterogeneity in telomere length of human chromosomes. Hum Mol Genet 5:685–691 (1996).
  26. Lo AW, Sprung CN, Fouladi B, Pedram M, Sabatier L, et al: Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells. Mol Cell Biol 22:4836–4850 (2002a).
  27. Lo AW, Sabatier L, Fouladi B, Pottier G, Ricoul M, Murnane JP: DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia 4:531–538 (2002b).
  28. Ma C, Looney JE, Leu TH, Hamlin JL: Organization and genesis of dihydrofolate reductase amplicons in the genome of a methotrexate-resistant Chinese hamster ovary cell line. Mol Cell Biol 8:2316–2327 (1988).
  29. Marcand S, Brevet V, Mann C, Gilson E: Cell cycle restriction of telomere elongation. Curr Biol 10:487–490 (2000).
  30. Martín M, Genescà A, Latre L, Jaco I, Taccioli GE, et al: Postreplicative joining of DNA double-strand breaks causes genomic instability in DNA-PKcs-deficient mouse embryonic fibroblasts. Cancer Res 65:10223–10232 (2005).
  31. McClintock B: The stability of broken ends of chromosomes in Zea mays. Genetics 26:234–282 (1941).
  32. Mondello C, Faravelli M, Pipitone L, Rollier A, Di Leonardo A, Giulotto E: Gene amplification in fibroblasts from ataxia telangiectasia (AT) patients and in X-ray hypersensitive AT-like Chinese hamster mutants. Carcinogenesis 22:141–145 (2001a).
  33. Mondello C, Rebuzzini P, Dolzan M, Edmonson S, Taccioli GE, Giulotto E: Increased gene amplification in immortal rodent cells deficient for the DNA-dependent protein kinase catalytic subunit. Cancer Res 61:4520–4525 (2001b).
  34. Mottolese M, Nádasi EA, Botti C, Cianciulli AM, Merola R, et al: Phenotypic changes of p53, HER2, and FAS system in multiple normal tissues surrounding breast cancer. J Cell Physiol 204:106–112 (2005).
  35. Murnane JP, Sabatier L: Chromosome rearrangements resulting from telomere dysfunction and their role in cancer. Bioessays 26:1164–1174 (2004).
  36. O’Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, et al: Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2:149–155 (2002).
  37. Ponsa I, Barquinero JF, Miró R, Egozcue J, Genescà A: Non-disjunction and chromosome loss in gamma-irradiated human lymphocytes: a fluorescence in situ hybridization analysis using centromere-specific probes. Radiat Res 155:424–431 (2001).
  38. Roh HJ, Shin DM, Lee JS, Ro JY, Tainsky MA, et al: Visualization of the timing of gene amplification during multistep head and neck tumorigenesis. Cancer Res 60:6496–6502 (2000).
  39. Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD: Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409:633–637 (2001).
  40. Sabatier L, Ricoul M, Pottier G, Murnane JP: The loss of a single telomere can result in instability of multiple chromosomes in a human tumor cell line. Mol Cancer Res 3:139–150 (2005).
  41. Savelyeva L, Schwab M: Amplification of oncogenes revisited: from expression profiling to clinical application. Cancer Lett 167:115–123 (2001).
  42. Shimizu N, Shingaki K, Kaneko-Sasaguri Y, Hashizume T, Kanda T: When, where and how the bridge breaks: anaphase bridge breakage plays a crucial role in gene amplification and HSR generation. Exp Cell Res 302:233–243 (2005).
  43. Sjögren C, Nasmyth K: Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr Biol 11:991–995 (2001).
  44. Soler D, Genescà A, Arnedo G, Egozcue J, Tusell L: Telomere dysfunction drives chromosomal instability in human mammary epithelial cells. Genes Chromosomes Cancer 44:339–350 (2005).
  45. Toledo F, Le Roscouet D, Buttin G, Debatisse M: Co-amplified markers alternate in megabase long chromosomal inverted repeats and cluster independently in interphase nuclei at early steps of mammalian gene amplification. EMBO J 11:2665–2673 (1992).
  46. Toledo F, Buttin G, Debatisse M: The origin of chromosome rearrangements at early stages of AMPD2 gene amplification in Chinese hamster cells. Curr Biol 3:255–264 (1993).
  47. Wahl GM: The importance of circular DNA in mammalian gene amplification. Cancer Res 49:1333–1340 (1989).
  48. Wang TL, Diaz LA Jr, Romans K, Bardelli A, Saha S, et al: Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl Acad Sci USA 101:3089–3094 (2004).
  49. Wazer DE, Chu Q, Liu XL, Gao Q, Safaii H, Band V: Loss of p53 protein during radiation transformation of primary human mammary epithelial cells. Mol Cell Biol 14:2468–2478 (1994).

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