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BioMed Research International
Volume 2013 (2013), Article ID 730714, 9 pages
http://dx.doi.org/10.1155/2013/730714
Review Article

Genome Instability at Common Fragile Sites: Searching for the Cause of Their Instability

Section of Molecular Epidemiology, Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy

Received 27 April 2013; Accepted 7 August 2013

Academic Editor: Abbas Dehghan

Copyright © 2013 Annapaola Franchitto. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. Branzei and M. Foiani, “Interplay of replication checkpoints and repair proteins at stalled replication forks,” DNA Repair, vol. 6, no. 7, pp. 994–1003, 2007. View at Publisher · View at Google Scholar · View at Scopus
  2. T. W. Glover, M. F. Arlt, A. M. Casper, and S. G. Durkin, “Mechanisms of common fragile site instability,” Human Molecular Genetics, vol. 14, no. 2, pp. R197–R205, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. F. Hecht and T. W. Glover, “Cancer chromosome breakpoints and common fragile sites induced by aphidicolin,” Cancer Genetics and Cytogenetics, vol. 13, no. 2, pp. 185–188, 1984. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Mangelsdorf, K. Ried, E. Woollatt et al., “Chromosomal fragile site FRA16D and DNA instability in cancer,” Cancer Research, vol. 60, no. 6, pp. 1683–1689, 2000. View at Scopus
  5. K. Mimori, T. Druck, H. Inoue et al., “Cancer-specific chromosome alterations in the constitutive fragile region FRA3B,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7456–7461, 1999. View at Publisher · View at Google Scholar · View at Scopus
  6. J. J. Yunis and A. L. Soreng, “Constitutive fragile sites and cancer,” Science, vol. 226, no. 4679, pp. 1199–1204, 1984. View at Scopus
  7. V. G. Gorgoulis, L.-V. F. Vassiliou, P. Karakaidos et al., “Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions,” Nature, vol. 434, no. 7035, pp. 907–913, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. K. Myung and R. D. Kolodner, “Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 7, pp. 4500–4507, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. S. Negrini, V. G. Gorgoulis, and T. D. Halazonetis, “Genomic instability an evolving hallmark of cancer,” Nature Reviews Molecular Cell Biology, vol. 11, no. 3, pp. 220–228, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Branzei and M. Foiani, “The checkpoint response to replication stress,” DNA Repair, vol. 8, no. 9, pp. 1038–1046, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. D. Branzei and M. Foiani, “Maintaining genome stability at the replication fork,” Nature Reviews Molecular Cell Biology, vol. 11, no. 3, pp. 208–219, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. J. Surrallés, S. P. Jackson, M. Jasin, M. B. Kastan, S. C. West, and H. Joenje, “Molecular cross-talk among chromosome fragility syndromes,” Genes and Development, vol. 18, no. 12, pp. 1359–1370, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Debatisse, B. Le Tallec, A. Letessier, B. Dutrillaux, and O. Brison, “Common fragile sites: mechanisms of instability revisited,” Trends in Genetics, vol. 28, no. 1, pp. 22–32, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. T. W. Glover, C. Berger, J. Coyle, and B. Echo, “DNA polymerase α inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes,” Human Genetics, vol. 67, no. 2, pp. 136–142, 1984. View at Scopus
  15. S. R. Denison, R. K. Simper, and I. F. Greenbaum, “How common are common fragile sites in humans: interindividual variation in the distribution of aphidicolin-induced fragile sites,” Cytogenetic and Genome Research, vol. 101, no. 1, pp. 8–16, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. D. Smeets, J. Scheres, and T. Hustinx, “The most common fragile site in man is 3p14,” Human Genetics, vol. 74, no. 3, p. 330, 1986. View at Publisher · View at Google Scholar · View at Scopus
  17. M. M. Le Beau, F. V. Rassool, M. E. Neilly et al., “Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction,” Human Molecular Genetics, vol. 7, no. 4, pp. 755–761, 1998. View at Publisher · View at Google Scholar · View at Scopus
  18. L. Wang, J. Darling, J.-S. Zhang, H. Huang, W. Liu, and D. I. Smith, “Allele-specific late replication and fragility of the most active common fragile site, FRA3B,” Human Molecular Genetics, vol. 8, no. 3, pp. 431–437, 1999. View at Scopus
  19. A. Hellman, A. Rahat, S. W. Scherer, A. Darvasi, L.-C. Tsui, and B. Kerem, “Replication delay along FRA7H, a common fragile site on human chromosome 7, leads to chromosomal instability,” Molecular and Cellular Biology, vol. 20, no. 12, pp. 4420–4427, 2000. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Palakodeti, Y. Han, Y. Jiang, and M. M. Le Beau, “The role of late/slow replication of the FRA16D in common fragile site induction,” Genes Chromosomes and Cancer, vol. 39, no. 1, pp. 71–76, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Palakodeti, I. Lucas, Y. Jiang et al., “Impaired replication dynamics at the FRA3B common fragile site,” Human Molecular Genetics, vol. 19, no. 1, pp. 99–110, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. F. Pelliccia, N. Bosco, A. Curatolo, and A. Rocchi, “Replication timing of two human common fragile sites: FRA1H and FRA2G,” Cytogenetic and Genome Research, vol. 121, no. 3-4, pp. 196–200, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. E. Zlotorynski, A. Rahat, J. Skaug et al., “Molecular basis for expression of common and rare fragile sites,” Molecular and Cellular Biology, vol. 23, no. 20, pp. 7143–7151, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. T. Lukusa and J. P. Fryns, “Human chromosome fragility,” Biochimica et Biophysica Acta, vol. 1779, no. 1, pp. 3–16, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Schwartz, E. Zlotorynski, and B. Kerem, “The molecular basis of common and rare fragile sites,” Cancer Letters, vol. 232, no. 1, pp. 13–26, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. H. Zhang and C. H. Freudenreich, “An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae,” Molecular Cell, vol. 27, no. 3, pp. 367–379, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. R. L. Ragland, M. W. Glynn, M. F. Arlt, and T. W. Glover, “Stably transfected common fragile site sequences exhibit instability at ectopic sites,” Genes Chromosomes and Cancer, vol. 47, no. 10, pp. 860–872, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. L. M. Pirzio, P. Pichierri, M. Bignami, and A. Franchitto, “Werner syndrome helicase activity is essential in maintaining fragile site stability,” Journal of Cell Biology, vol. 180, no. 2, pp. 305–314, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. S. N. Shah, P. L. Opresko, X. Meng, M. Y. W. T. Lee, and K. A. Eckert, “DNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D,” Nucleic Acids Research, vol. 38, no. 4, pp. 1149–1162, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. A. Letessier, G. A. Millot, S. Koundrioukoff et al., “Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site,” Nature, vol. 470, no. 7332, pp. 120–123, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. B. Le Tallec, B. Dutrillaux, A.-M. Lachages, G. A. Millot, O. Brison, and M. Debatisse, “Molecular profiling of common fragile sites in human fibroblasts,” Nature Structural and Molecular Biology, vol. 18, no. 12, pp. 1421–1423, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. E. Ozeri-Galai, R. Lebofsky, A. Rahat, A. C. Bester, A. Bensimon, and B. Kerem, “Failure of origin activation in response to fork stalling leads to chromosomal instability at fragile sites,” Molecular Cell, vol. 43, no. 1, pp. 122–131, 2011. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Aguilera and T. García-Muse, “R loops: from transcription byproducts to threats to genome stability,” Molecular Cell, vol. 46, no. 2, pp. 115–124, 2012. View at Publisher · View at Google Scholar · View at Scopus
  34. A. Helmrich, M. Ballarino, and L. Tora, “Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes,” Molecular Cell, vol. 44, no. 6, pp. 966–977, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. R. T. Abraham, “Cell cycle checkpoint signaling through the ATM and ATR kinases,” Genes and Development, vol. 15, no. 17, pp. 2177–2196, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. L. Zou and S. J. Elledge, “Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes,” Science, vol. 300, no. 5625, pp. 1542–1548, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. A. M. Casper, P. Nghiem, M. F. Arlt, and T. W. Glover, “ATR regulates fragile site stability,” Cell, vol. 111, no. 6, pp. 779–789, 2002. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Budzowska and R. Kanaar, “Mechanisms of dealing with DNA damage-induced replication problems,” Cell Biochemistry and Biophysics, vol. 53, no. 1, pp. 17–31, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. D. S. Dimitrova and D. M. Gilbert, “Stability and nuclear distribution of mammalian replication protein A heterotrimeric complex,” Experimental Cell Research, vol. 254, no. 2, pp. 321–327, 2000. View at Publisher · View at Google Scholar · View at Scopus
  40. M. Lopes, C. Cotta-Ramusino, A. Pellicioli et al., “The DNA replication checkpoint response stabilizes stalled replication forks,” Nature, vol. 412, no. 6846, pp. 557–561, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. J. A. Tercero and J. F. X. Diffley, “Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint,” Nature, vol. 412, no. 6846, pp. 553–557, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. A. M. Casper, S. G. Durkin, M. F. Arlt, and T. W. Glover, “Chromosomal instability at common fragile sites in seckel syndrome,” American Journal of Human Genetics, vol. 75, no. 4, pp. 654–660, 2004. View at Publisher · View at Google Scholar · View at Scopus
  43. C. Wan, A. Kulkarni, and Y.-H. Wang, “ATR preferentially interacts with common fragile site FRA3B and the binding requires its kinase activity in response to aphidicolin treatment,” Mutation Research, vol. 686, no. 1-2, pp. 39–46, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. S. G. Durkin and T. W. Glover, “Chromosome fragile sites,” Annual Review of Genetics, vol. 41, pp. 169–192, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Zhu and R. S. Weiss, “Increased common fragile site expression, cell proliferation defects, and apoptosis following conditional inactivation of mouse Hus1 in primary cultured cells,” Molecular Biology of the Cell, vol. 18, no. 3, pp. 1044–1055, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. M. L. Focarelli, S. Soza, L. Mannini, M. Paulis, A. Montecucco, and A. Musio, “Claspin inhibition leads to fragile site expression,” Genes Chromosomes and Cancer, vol. 48, no. 12, pp. 1083–1090, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. C. Feijoo, C. Hall-Jackson, R. Wu et al., “Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing,” Journal of Cell Biology, vol. 154, no. 5, pp. 913–923, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. E. Petermann, A. Maya-Mendoza, G. Zachos, D. A. F. Gillespie, D. A. Jackson, and K. W. Caldecott, “Chk1 requirement for high global rates of replication fork progression during normal vertebrate S phase,” Molecular and Cellular Biology, vol. 26, no. 8, pp. 3319–3326, 2006. View at Publisher · View at Google Scholar · View at Scopus
  49. C. S. Sørensen, R. G. Syljuåsen, J. Lukas, and J. Bartek, “ATR, claspin and the Rad9-Rad1-Hus1 complex Chk1 and Cdc25A in the absence of DNA damage,” Cell Cycle, vol. 3, no. 7, pp. 941–945, 2004. View at Scopus
  50. F. Ammazzalorso, L. M. Pirzio, M. Bignami, A. Franchitto, and P. Pichierri, “ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery,” EMBO Journal, vol. 29, no. 18, pp. 3156–3169, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. M. L. Rossi, A. K. Ghosh, and V. A. Bohr, “Roles of Werner syndrome protein in protection of genome integrity,” DNA Repair, vol. 9, no. 3, pp. 331–344, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. I. Murfuni, A. De Santis, M. Federico, et al., “Perturbed replication induced genome wide or at common fragile sites is differently managed in the absence of WRN,” Carcinogenesis, vol. 33, pp. 1655–1663, 2012.
  53. A. S. Kamath-Loeb, L. A. Loeb, E. Johansson, P. M. J. Burgers, and M. Fry, “Interactions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence,” Journal of Biological Chemistry, vol. 276, no. 19, pp. 16439–16446, 2001. View at Publisher · View at Google Scholar · View at Scopus
  54. C. S. Sørensen, L. T. Hansen, J. Dziegielewski et al., “The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair,” Nature Cell Biology, vol. 7, no. 2, pp. 195–201, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Hashimoto, A. R. Chaudhuri, M. Lopes, and V. Costanzo, “Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis,” Nature Structural and Molecular Biology, vol. 17, no. 11, pp. 1305–1311, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Schwartz, E. Zlotorynski, M. Goldberg et al., “Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability,” Genes and Development, vol. 19, no. 22, pp. 2715–2726, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. K. L. Chan, T. Palmai-Pallag, S. Ying, and I. D. Hickson, “Replication stress induces sister-chromatid bridging at fragile site loci in mitosis,” Nature Cell Biology, vol. 11, no. 6, pp. 753–760, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. V. Naim and F. Rosselli, “The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities,” Nature Cell Biology, vol. 11, no. 6, pp. 761–768, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. K. Gari, C. Décaillet, A. Z. Stasiak, A. Stasiak, and A. Constantinou, “The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks,” Molecular Cell, vol. 29, no. 1, pp. 141–148, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. N. G. Howlett, T. Taniguchi, S. G. Durkin, A. D. D'Andrea, and T. W. Glover, “The Fanconi anemia pathway is required for the DNA replication stress respone and for the regulation of common fragile site stability,” Human Molecular Genetics, vol. 14, no. 5, pp. 693–701, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. A. R. Meetei, S. Sechi, M. Wallisch et al., “A multiprotein nuclear complex connects fanconi anemia and bloom syndrome,” Molecular and Cellular Biology, vol. 23, no. 10, pp. 3417–3426, 2003. View at Publisher · View at Google Scholar · View at Scopus
  62. P. Pichierri, A. Franchitto, and F. Rosselli, “BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks,” EMBO Journal, vol. 23, no. 15, pp. 3154–3163, 2004. View at Publisher · View at Google Scholar · View at Scopus
  63. A. N. Suhasini and R. M. Brosh Jr., “Fanconi anemia and Bloom's syndrome crosstalk through FANCJ-BLM helicase interaction,” Trends in Genetics, vol. 28, no. 1, pp. 7–13, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Munoz-Galvan, C. Tous, M. G. Blanco, et al., “Distinct roles of Mus81, Yen1, Slx1-Slx4, and Rad1 nucleases in the repair of replication-born double-strand breaks by sister chromatid exchange,” Molecular and Cellular Biology, vol. 32, pp. 1592–1603, 2012.
  65. I. Murfuni, S. Nicolai, S. Baldari et al., “The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation,” Oncogene, vol. 32, no. 5, pp. 610–620, 2013. View at Publisher · View at Google Scholar · View at Scopus