Chromosome Research

, 15:1061 | Cite as

Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells

  • Lura Brianna Caddle
  • Jeremy L. Grant
  • Jin Szatkiewicz
  • Johann van Hase
  • Bobbi-Jo Shirley
  • Joerg Bewersdorf
  • Christoph Cremer
  • Alain Arneodo
  • Andre Khalil
  • Kevin D. Mills
Article

Abstract

Radiation exposure is an occupational hazard for military personnel, some health care professionals, airport security screeners, and medical patients, with some individuals at risk for acute, high-dose exposures. Therefore, the biological effects of radiation, especially the potential for chromosome damage, are major occupational and health concerns. However, the biophysical mechanisms of chromosome instability subsequent to radiation-induced DNA damage are poorly understood. It is clear that interphase chromosomes occupy discrete structural and functional subnuclear domains, termed chromosome territories (CT), which may be organized into ‘neighborhoods’ comprising groups of specific CTs. We directly evaluated the relationship between chromosome positioning, neighborhood composition, and translocation partner choice in primary lymphocytes, using a cell-based system in which we could induce multiple, concentrated DNA breaks via high-dose irradiation. We critically evaluated mis-rejoining profiles and tested whether breaks occurring nearby were more likely to fuse than breaks occurring at a distance. We show that CT neighborhoods comprise heterologous chromosomes, within which inter-CT distances directly relate to translocation partner choice. These findings demonstrate that interphase chromosome arrangement is a principal factor in genomic instability outcomes in primary lymphocytes, providing a structural context for understanding the biological effects of radiation exposure, and the molecular etiology of tumor-specific translocation patterns.

Key words

chromosome positioning nuclear domain primary cells p53 radiation translocation 

References

  1. Arsuaga J, Greulich-Bode KM, Vazquez M et al. (2004) Chromosome spatial clustering inferred from radiogenic aberrations. Int J Radiat Biol 80: 507–15.CrossRefPubMedGoogle Scholar
  2. Aten JA, Stap J, Krawczyk PM et al. (2004) Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 303: 92–5.CrossRefPubMedGoogle Scholar
  3. Berr A, Pecinka A, Meister A et al. (2006) Chromosome arrangement and nuclear architecture but not centromeric sequences are conserved between Arabidopsis thaliana and Arabidopsis lyrata. Plant J 48: 771–83.CrossRefPubMedGoogle Scholar
  4. Bickmore WA, Teague P (2002) Influences of chromosome size, gene density and nuclear position on the frequency of constitutional translocations in the human population. Chromosome Res 10: 707–15.CrossRefPubMedGoogle Scholar
  5. Branco MR, Pombo A (2006) Intermingling of chromosome territories in interphase suggests role in translocations and transcription-dependent associations. PLoS Biol 4: e138.CrossRefPubMedGoogle Scholar
  6. Chaikin PM, Donev A, Man W, Stillinger FH and Torquato S (2006) Some observations on the random packing of hard ellipsoids. Ind Eng Chem Res 45: 6960–965.CrossRefGoogle Scholar
  7. Cornforth MN (2006) Perspectives on the formation of radiation-induced exchange aberrations. DNA Repair (Amst) 5: 1182–191.CrossRefGoogle Scholar
  8. Cornforth MN, Greulich-Bode KM, Loucas BD et al. (2002) Chromosomes are predominantly located randomly with respect to each other in interphase human cells. J Cell Biol 159: 237–44.CrossRefPubMedGoogle Scholar
  9. Couedel C, Mills KD, MBarchi KD et al. (2004) Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells. Genes Dev 18: 1293–304.CrossRefPubMedGoogle Scholar
  10. Cremer T, Cremer C (2001) Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat Rev Genet 2: 292–01.CrossRefPubMedGoogle Scholar
  11. Cremer T, Kreth G, Koester H et al. (2000) Chromosome territories, interchromatin domain compartment, and nuclear matrix: an integrated view of the functional nuclear architecture. Crit Rev Eukaryot Gene Expr 10: 179–12.PubMedGoogle Scholar
  12. Cremer M, Kupper K, Wagler B et al. (2003) Inheritance of gene density-related higher order chromatin arrangements in normal and tumor cell nuclei. J Cell Biol 162: 809–20.CrossRefPubMedGoogle Scholar
  13. Donehower LA, Harvey M, Slagle BL et al. (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–21.CrossRefPubMedGoogle Scholar
  14. Donev A, Cisse I, Sachs D et al. (2004) Improving the density of jammed disordered packings using ellipsoids. Science 303: 990–93.CrossRefPubMedGoogle Scholar
  15. Dundr M, Misteli T (2001) Functional architecture in the cell nucleus. Biochem J 356: 297–10.CrossRefPubMedGoogle Scholar
  16. Gilbert N, Boyle S, Fiegler H, Woodfine K, Carter NP, Bickmore WA (2004) Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell 118: 555–66.CrossRefPubMedGoogle Scholar
  17. Gilbert N, Gilchrist S, Bickmore WA (2005) Chromatin organization in the mammalian nucleus. Int Rev Cytol 242: 283–36.CrossRefPubMedGoogle Scholar
  18. Hlatky L, Sachs RK, Vazquez M, Cornforth MN (2002) Radiation-induced chromosome aberrations: insights gained from biophysical modeling. Bioessays 24: 714–23.CrossRefPubMedGoogle Scholar
  19. Hochberg Y (1988) A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75: 800–02.CrossRefGoogle Scholar
  20. Hope ACA (1968) A simplified Monte Carlo significance test procedure. Journal of the Royal Statistical Society B 30: 582–98.Google Scholar
  21. Khalil A, Grant JL, Caddle LB, Aztema E, Mills KD, Arneodo A (in press) Chromosome territories have a highly nonspherical morphology and nonrandom positioning. Chromosome Res. Google Scholar
  22. Kreth G, Finsterle J, von Hase J, Cremer M, Cremer C (2004) Radial arrangement of chromosome territories in human cell nuclei: a computer model approach based on gene density indicates a probabilistic global positioning code. Biophys J 86: 2803–812.CrossRefPubMedGoogle Scholar
  23. Meaburn KJ, Misteli T (2007) Cell biology: chromosome territories. Nature 445: 379–81.CrossRefPubMedGoogle Scholar
  24. Meaburn K, Misteli JT, Soutoglou E (2007) Spatial genome organization in the formation of chromosomal translocations. Semin Cancer Biol 17: 80–0.CrossRefPubMedGoogle Scholar
  25. Mills KD, Ferguson DO, Essers J, Eckersdorff M, Kanaar R, Alt FW (2004) Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability. Genes Dev 18: 1283–2.CrossRefPubMedGoogle Scholar
  26. Mora L, Sanchez I, Garcia M, Ponsa M (2006) Chromosome territory positioning of conserved homologous chromosomes in different primate species. Chromosoma 115: 367–75.CrossRefPubMedGoogle Scholar
  27. Murmann AE, Gao J, Encinosa M et al. (2005) Local gene density predicts the spatial position of genetic loci in the interphase nucleus. Exp Cell Res 311: 14–6.CrossRefPubMedGoogle Scholar
  28. Osborne CS, Chakalova L, Mitchell JA et al. (2007) Myc dynamically and preferentially relocates to a transcription factory occupied by Igh. PLoS Biol 5: e192.CrossRefPubMedGoogle Scholar
  29. Parada L, Misteli T (2002) Chromosome positioning in the interphase nucleus. Trends Cell Biol 12: 425–32.CrossRefPubMedGoogle Scholar
  30. Parada LA, McQueen PG, Misteli T (2004a) Tissue-specific spatial organization of genomes. Genome Biol 5: R44.CrossRefGoogle Scholar
  31. Parada LA, Sotiriou S, Misteli T (2004b) Spatial genome organization. Exp Cell Res 296: 64–0.CrossRefGoogle Scholar
  32. Shopland LS, Lynch CR, Peterson KA et al. (2006) Folding and organization of a contiguous chromosome region according to the gene distribution pattern in primary genomic sequence. J Cell Biol 174: 27–8.CrossRefPubMedGoogle Scholar
  33. Stadler S, Schnapp V, Mayer R et al. (2004) The architecture of chicken chromosome territories changes during differentiation. BMC Cell Biol 5: 44.CrossRefPubMedGoogle Scholar
  34. Tanabe H, Muller S, Neusser M et al. (2002) Evolutionary conservation of chromosome territory arrangements in cell nuclei from higher primates. Proc Natl Acad Sci USA 99: 4424–429.CrossRefPubMedGoogle Scholar
  35. Thomson I, Gilchrist S, Bickmore WA, Chubb JR (2004) The radial positioning of chromatin is not inherited through mitosis but is established de novo in early G1. Curr Biol 14: 166–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Lura Brianna Caddle
    • 1
  • Jeremy L. Grant
    • 2
  • Jin Szatkiewicz
    • 1
  • Johann van Hase
    • 3
  • Bobbi-Jo Shirley
    • 1
  • Joerg Bewersdorf
    • 4
  • Christoph Cremer
    • 3
    • 4
  • Alain Arneodo
    • 4
    • 5
  • Andre Khalil
    • 2
    • 4
  • Kevin D. Mills
    • 1
    • 4
  1. 1.The Jackson LaboratoryBar HarborUSA
  2. 2.Department of Mathematics & StatisticsUniversity of MaineOronoUSA
  3. 3.Kirchhoff Institute for PhysicsUniversity of HeidelbergHeidelbergGermany
  4. 4.Institute for Molecular BiophysicsUniversity of MaineOronoUSA
  5. 5.Laboratoire Joliot Curie et Laboratoire de PhysiqueEcole Normale Supérieure de Lyon (CNRS)Lyon Cedex 07France

Personalised recommendations