Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Palindromic gene amplification — an evolutionarily conserved role for DNA inverted repeats in the genome

Abstract

The clinical importance of gene amplification in the diagnosis and treatment of cancer has been widely recognized, as it is often evident in advanced stages of diseases. However, our knowledge of the underlying mechanisms is still limited. Gene amplification is an essential process in several organisms including the ciliate Tetrahymena thermophila, in which the initiating mechanism has been well characterized. Lessons from such simple eukaryotes may provide useful information regarding how gene amplification occurs in tumour cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Breakage–fusion–bridge (BFB) cycles.
Figure 2: Palindromic gene amplification in the ciliated protozoan Tetrahymena thermophila.
Figure 3: Molecular mechanisms generating a large DNA palindrome from a pre-existing DNA inverted repeat (DNA-IR) in yeast.
Figure 4: Potential genetic factors suppressing palindromic gene amplification in human cells.

Similar content being viewed by others

References

  1. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Lobrich, M. & Jeggo, P. A. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nature Rev. Cancer 7, 861–869 (2007).

    Article  CAS  Google Scholar 

  3. Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. Di Fiore, P. P. et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237, 178–182 (1987).

    Article  CAS  PubMed  Google Scholar 

  5. Muller, W. J., Sinn, E., Pattengale, P. K., Wallace, R. & Leder, P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54, 105–115 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR–ABL gene mutation or amplification. Science 293, 876–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Brodeur, G. M., Seeger, R. C., Schwab, M., Varmus, H. E. & Bishop, J. M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224, 1121–1124 (1984).

    Article  CAS  PubMed  Google Scholar 

  8. Holst, F. et al. Estrogen receptor α (ESR1) gene amplification is frequent in breast cancer. Nature Genet. 39, 655–660 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Mariani, O. et al. JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas. Cancer Cell 11, 361–374 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. van der Horst, E. H. et al. Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1. Proc. Natl Acad. Sci. USA 102, 15901–15906 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Goker, E. et al. Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 86, 677–684 (1995).

    CAS  PubMed  Google Scholar 

  13. Wang, T. L. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pinkel, D. & Albertson, D. G. Array comparative genomic hybridization and its applications in cancer. Nature Genet. 37 (Suppl), S11–S17 (2005).

    Google Scholar 

  15. Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Hicks, J. et al. Novel patterns of genome rearrangement and their association with survival in breast cancer. Genome Res. 16, 1465–1479 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McClintock, B. The stability of broken ends of chromosomes in Zea mays. Genetics 26, 234–282 (1941).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Trask, B. J. & Hamlin, J. L. Early dihydrofolate reductase gene amplification events in CHO cells usually occur on the same chromosome arm as the original locus. Genes Dev. 3, 1913–1925 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Smith, K. A., Gorman, P. A., Stark, M. B., Groves, R. P. & Stark, G. R. Distinctive chromosomal structures are formed very early in the amplification of CAD genes in Syrian hamster cells. Cell 63, 1219–1227 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ciullo, M. et al. Initiation of the breakage-fusion-bridge mechanism through common fragile site activation in human breast cancer cells: the model of PIP gene duplication from a break at FRA7I. Hum. Mol. Genet. 11, 2887–2894 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Hellman, A. et al. A role for common fragile site induction in amplification of human oncogenes. Cancer Cell 1, 89–97 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Shuster, M. I. et al. A consistent pattern of RIN1 rearrangements in oral squamous cell carcinoma cell lines supports a breakage-fusion-bridge cycle model for 11q13 amplification. Genes Chromosomes Cancer 28, 153–163 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Coquelle, A., Pipiras, E., Toledo, F., Buttin, G. & Debatisse, M. Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell 89, 215–225 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Lo, A. W. et al. DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia 4, 531–538 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Murnane, J. P. & Sabatier, L. Chromosome rearrangements resulting from telomere dysfunction and their role in cancer. Bioessays 26, 1164–1174 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. Nonet, G. H., Carroll, S. M., DeRose, M. L. & Wahl, G. M. Molecular dissection of an extrachromosomal amplicon reveals a circular structure consisting of an imperfect inverted duplication. Genomics 15, 543–558 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Wahl, G. M. The importance of circular DNA in mammalian gene amplification. Cancer Res. 49, 1333–1340 (1989).

    CAS  PubMed  Google Scholar 

  30. Bignell, G. R. et al. Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res. 17, 1296–1303 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Volik, S. et al. Decoding the fine-scale structure of a breast cancer genome and transcriptome. Genome Res. 16, 394–404 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lo, A. W. et al. Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells. Mol. Cell. Biol. 22, 4836–4850 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Okuno, Y., Hahn, P. J. & Gilbert, D. M. Structure of a palindromic amplicon junction implicates microhomology-mediated end joining as a mechanism of sister chromatid fusion during gene amplification. Nucleic Acids Res. 32, 749–756 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brown, D. D. & Dawid, I. B. Specific gene amplification in oocytes. Oocyte nuclei contain extrachromosomal replicas of the genes for ribosomal RNA. Science 160, 272–280 (1968).

    Article  CAS  PubMed  Google Scholar 

  35. Gall, J. G., Macgregor, H. C. & Kidston, M. E. Gene amplification in the oocytes of Dytiscid water beetles. Chromosoma 26, 169–187 (1969).

    Article  CAS  PubMed  Google Scholar 

  36. Spradling, A. C. The organization and amplification of two chromosomal domains containing Drosophila chorion genes. Cell 27, 193–201 (1981).

    Article  CAS  PubMed  Google Scholar 

  37. Stark, G. R., Debatisse, M., Giulotto, E. & Wahl, G. M. Recent progress in understanding mechanisms of mammalian DNA amplification. Cell 57, 901–908 (1989).

    Article  CAS  PubMed  Google Scholar 

  38. Yao, M. C. & Gorovsky, M. A. Comparison of the sequences of macro- and micronuclear DNA of Tetrahymena pyriformis. Chromosoma 48, 1–18 (1974).

    Article  CAS  PubMed  Google Scholar 

  39. Yao, M. C., Yao, C. H. & Monks, B. The controlling sequence for site-specific chromosome breakage in Tetrahymena. Cell 63, 763–772 (1990).

    Article  CAS  PubMed  Google Scholar 

  40. Yasuda, L. F. & Yao, M. C. Short inverted repeats at a free end signal large palindromic DNA formation in Tetraihymena. Cell 67, 505–516 (1991).

    Article  CAS  PubMed  Google Scholar 

  41. Yao, M. C. & Chao, J. L. RNA-guided DNA deletion in Tetrahymena: an RNAi-based mechanism for programmed genome rearrangements. Annu. Rev. Genet. 39, 537–559 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Butler, D. K., Yasuda, L. E. & Yao, M. C. An intramolecular recombination mechanism for the formation of the rRNA gene palindrome of Tetrahymena thermophila. Mol. Cell. Biol. 15, 7117–7126 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Butler, D. K., Yasuda, L. E. & Yao, M. C. Induction of large DNA palindrome formation in yeast: implications for gene amplification and genome stability in eukaryotes. Cell 87, 1115–1122 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Tanaka, H., Tapscott, S. J., Trask, B. J. & Yao, M. C. Short inverted repeats initiate gene amplification through the formation of a large DNA palindrome in mammalian cells. Proc. Natl Acad. Sci. USA 99, 8772–8777 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Haber, J. E. & Debatisse, M. Gene amplification: yeast takes a turn. Cell 125, 1237–1240 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Ira, G. et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431, 1011–1017 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Huertas, P., Cortes-Ledesma, F., Sartori, A. A., Aguilera, A. & Jackson, S. P. CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455, 689–692 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mimitou, E. P. & Symington, L. S. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455, 770–774 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Zhu, Z., Chung, W. H., Shim, E. Y., Lee, S. E. & Ira, G. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134, 981–994 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Maringele, L. & Lydall, D. Telomerase- and recombination-independent immortalization of budding yeast. Genes Dev. 18, 2663–2675 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Linardopoulou, E. V. et al. Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437, 94–100 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. der-Sarkissian, H., Bacchetti, S., Cazes, L. & Londono-Vallejo, J. A. The shortest telomeres drive karyotype evolution in transformed cells. Oncogene 23, 1221–1228 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Soler, D., Genesca, A., Arnedo, G., Egozcue, J. & Tusell, L. Telomere dysfunction drives chromosomal instability in human mammary epithelial cells. Genes Chromosomes Cancer 44, 339–350 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Lobachev, K. S., Gordenin, D. A. & Resnick, M. A. The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell 108, 183–193 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Stenger, J. E. et al. Biased distribution of inverted and direct Alus in the human genome: implications for insertion, exclusion, and genome stability. Genome Res. 11, 12–27 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Cote, A. G. & Lewis, S. M. Mus81-dependent double-strand DNA breaks at in vivo-generated cruciform structures in S. cerevisiae. Mol. Cell 31, 800–812 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Lemoine, F. J., Degtyareva, N. P., Lobachev, K. & Petes, T. D. Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites. Cell 120, 587–598 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Narayanan, V., Mieczkowski, P. A., Kim, H. M., Petes, T. D. & Lobachev, K. S. The pattern of gene amplification is determined by the chromosomal location of hairpin-capped breaks. Cell 125, 1283–1296 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Voineagu, I., Narayanan, V., Lobachev, K. S. & Mirkin, S. M. Replication stalling at unstable inverted repeats: interplay between DNA hairpins and fork stabilizing proteins. Proc. Natl Acad. Sci. USA 105, 9936–9941 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zheng, L. et al. Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks. EMBO Rep. 6, 83–89 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Rattray, A. J., Shafer, B. K., Neelam, B. & Strathern, J. N. A mechanism of palindromic gene amplification in Saccharomyces cerevisiae. Genes Dev. 19, 1390–1399 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Watanabe, T. & Horiuchi, T. A novel gene amplification system in yeast based on double rolling-circle replication. EMBO J. 24, 190–198 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Mortensen, U. H., Bendixen, C., Sunjevaric, I. & Rothstein, R. DNA strand annealing is promoted by the yeast Rad52 protein. Proc. Natl Acad. Sci. USA 93, 10729–10734 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Furuse, M. et al. Distinct roles of two separable in vitro activities of yeast Mre11 in mitotic and meiotic recombination. EMBO J. 17, 6412–6425 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Moreau, S., Ferguson, J. R. & Symington, L. S. The nuclease activity of Mre11 is required for meiosis but not for mating type switching, end joining, or telomere maintenance. Mol. Cell. Biol. 19, 556–566 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Paull, T. T. & Gellert, M. The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Mol. Cell 1, 969–979 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Trujillo, K. M., Yuan, S. S., Lee, E. Y. & Sung, P. Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95. J. Biol. Chem. 273, 21447–21450 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Lengsfeld, B. M., Rattray, A. J., Bhaskara, V., Ghirlando, R. & Paull, T. T. Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Mol. Cell 28, 638–651 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Giannini, G. et al. Human MRE11 is inactivated in mismatch repair-deficient cancers. EMBO Rep. 3, 248–254 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Miquel, C. et al. Frequent alteration of DNA damage signalling and repair pathways in human colorectal cancers with microsatellite instability. Oncogene 26, 5919–5926 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Mondello, C. et al. Increased gene amplification in immortal rodent cells deficient for the DNA-dependent protein kinase catalytic subunit. Cancer Res. 61, 4520–4525 (2001).

    CAS  PubMed  Google Scholar 

  72. Zhu, C. et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109, 811–821 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. VanHulle, K. et al. Inverted DNA repeats channel repair of distant double-strand breaks into chromatid fusions and chromosomal rearrangements. Mol. Cell. Biol. 27, 2601–2614 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Downing, B., Morgan, R., VanHulle, K., Deem, A. & Malkova, A. Large inverted repeats in the vicinity of a single double-strand break strongly affect repair in yeast diploids lacking Rad51. Mutat. Res. 645, 9–18 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Darlow, J. M. & Leach, D. R. The effects of trinucleotide repeats found in human inherited disorders on palindrome inviability in Escherichia coli suggest hairpin folding preferences in vivo. Genetics 141, 825–832 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Moore, H., Greenwell, P. W., Liu, C. P., Arnheim, N. & Petes, T. D. Triplet repeats form secondary structures that escape DNA repair in yeast. Proc. Natl Acad. Sci. USA 96, 1504–1509 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kogo, H. et al. Cruciform extrusion propensity of human translocation-mediating palindromic AT-rich repeats. Nucleic Acids Res. 35, 1198–1208 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Warburton, P. E., Giordano, J., Cheung, F., Gelfand, Y. & Benson, G. Inverted repeat structure of the human genome: the X-chromosome contains a preponderance of large, highly homologous inverted repeats that contain testes genes. Genome Res. 14, 1861–1869 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Pentao, L., Wise, C. A., Chinault, A. C., Patel, P. I. & Lupski, J. R. Charcot–Marie–Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nature Genet. 2, 292–300 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Barbouti, A. et al. The breakpoint region of the most common isochromosome, i(17q), in human neoplasia is characterized by a complex genomic architecture with large, palindromic, low-copy repeats. Am. J. Hum. Genet. 74, 1–10 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Carvalho, C. M. & Lupski, J. R. Copy number variation at the breakpoint region of isochromosome 17q. Genome Res. (2008).

  83. She, X. et al. A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications. Genome Res. 16, 576–583 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Eykelenboom, J. K., Blackwood, J. K., Okely, E. & Leach, D. R. SbcCD causes a double-strand break at a DNA palindrome in the Escherichia coli chromosome. Mol. Cell 29, 644–651 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Payen, C., Koszul, R., Dujon, B. & Fischer, G. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLoS Genet. 4, e1000175 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Lee, J. A., Carvalho, C. M. & Lupski, J. R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Lupski, J. R. et al. DNA duplication associated with Charcot–Marie–Tooth disease type 1A. Cell 66, 219–232 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Sharp, A. J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Darai-Ramqvist, E. et al. Segmental duplications and evolutionary plasticity at tumor chromosome break-prone regions. Genome Res. 18, 370–379 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Camps, J. et al. Chromosomal breakpoints in primary colon cancer cluster at sites of structural variants in the genome. Cancer Res. 68, 1284–1295 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Murphy, W. J. et al. Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps. Science 309, 613–617 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Tanaka, H., Bergstrom, D. A., Yao, M. C. & Tapscott, S. J. Widespread and nonrandom distribution of DNA palindromes in cancer cells provides a structural platform for subsequent gene amplification. Nature Genet. 37, 320–327 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Tanaka, H. et al. Intrastrand annealing leads to the formation of a large DNA palindrome and determines the boundaries of genomic amplification in human cancer. Mol. Cell. Biol. 27, 1993–2002 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Margulies, M. et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437, 376–380 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Campbell, P. J. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genet. 40, 722–729 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Amler, L. C. & Schwab, M. Amplified N-myc in human neuroblastoma cells is often arranged as clustered tandem repeats of differently recombined DNA. Mol. Cell. Biol. 9, 4903–4913 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kuwahara, Y. et al. Alternative mechanisms of gene amplification in human cancers. Genes Chromosomes Cancer 41, 125–132 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Tlsty, T. D., White, A. & Sanchez, J. Suppression of gene amplification in human cell hybrids. Science 255, 1425–1427 (1992).

    Article  CAS  PubMed  Google Scholar 

  101. Livingstone, L. R. et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70, 923–935 (1992).

    Article  CAS  PubMed  Google Scholar 

  102. Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C. & Wahl, G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70, 937–948 (1992).

    Article  CAS  PubMed  Google Scholar 

  103. Saintigny, Y., Rouillard, D., Chaput, B., Soussi, T. & Lopez, B. S. Mutant p53 proteins stimulate spontaneous and radiation-induced intrachromosomal homologous recombination independently of the alteration of the transactivation activity and of the G1 checkpoint. Oncogene 18, 3553–3563 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Bertrand, P., Saintigny, Y. & Lopez, B. S. p53's double life: transactivation-independent repression of homologous recombination. Trends Genet. 20, 235–243 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Buis, J. et al. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135, 85–96 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sartori, A. A. et al. Human CtIP promotes DNA end resection. Nature 450, 509–514 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hampton, O. A. et al. A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. Genome Res. (2009).

  109. Yunis, J. J. & Soreng, A. L. Constitutive fragile sites and cancer. Science 226, 1199–1204 (1984).

    Article  CAS  PubMed  Google Scholar 

  110. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nature Rev. Cancer 7, 233–245 (2007).

    Article  CAS  Google Scholar 

  111. Waldman, A. S., Tran, H., Goldsmith, E. C. & Resnick, M. A. Long inverted repeats are an at-risk motif for recombination in mammalian cells. Genetics 153, 1873–1883 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kato, T. et al. Genetic variation affects de novo translocation frequency. Science 311, 971 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Haiman, C. A. et al. A common genetic risk factor for colorectal and prostate cancer. Nature Genet. 39, 954–956 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nature Genet. 39, 984–988 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Kallioniemi, A. et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258, 818–821 (1992).

    Article  CAS  PubMed  Google Scholar 

  116. Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genet. 20, 207–211 (1998).

    Article  CAS  PubMed  Google Scholar 

  117. Ishkanian, A. S. et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nature Genet. 36, 299–303 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Johnson, W. E. et al. Model-based analysis of tiling-arrays for ChIP-chip. Proc. Natl Acad. Sci. USA 103, 12457–12462 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. McCarroll, S. A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. (2008).

  120. Perry, G. H. et al. The fine-scale and complex architecture of human copy-number variation. Am. J. Hum. Genet. 82, 685–695 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Stemm-Wolf, A. J. et al. Basal body duplication and maintenance require one member of the Tetrahymena thermophila centrin gene family. Mol. Biol. Cell 16, 3606–3619 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hai, B. & Gorovsky, M. A. Germ-line knockout heterokaryons of an essential alpha-tubulin gene enable high-frequency gene replacement and a test of gene transfer from somatic to germ-line nuclei in Tetrahymena thermophila. Proc. Natl Acad. Sci. USA 94, 1310–1315 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Tapsoctt and S. Diede for useful discussions. We also thank G. Stark for critically reading the manuscript. This work is supported by the Cleveland Clinic Foundation (to H.T.) and by the Institute of Molecular Biology, Academia Sinica, and the National Research Council of Taiwan (to M.-C.Y.).

Author information

Authors and Affiliations

Authors

Supplementary information

Supplementary information S1 (box)

HSRs and DMs; two forms of amplified chromosomal regions (PDF 202 kb)

Related links

Related links

DATABASES

OMIM

Charcot–Marie–Tooth disease type 1A

FURTHER INFORMATION

Hisashi Tanaka's homepage

Meng-Chao Yao's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, H., Yao, MC. Palindromic gene amplification — an evolutionarily conserved role for DNA inverted repeats in the genome. Nat Rev Cancer 9, 216–224 (2009). https://doi.org/10.1038/nrc2591

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2591

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing