DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes (original) (raw)

Nature volume 484, pages 69–74 (2012)Cite this article

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Abstract

Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies.

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Sequence Read Archive

Data deposits

All sequence data are available at the NCBI SRA database under accession number SRP010565.

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Acknowledgements

We thank members of the Casellas and Nussenzweig laboratories for discussions; G. Gutierrez from NIAMS genomics facility for technical assistance. This work was supported in part by NIH grant number AI037526 to M.C.N. and the Intramural Research Program of NIAMS and NCI, NIH. M.C.N. is an HHMI investigator. This study made use of the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov), and the resources of NCI’s High-Throughput Imaging Facility.

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Author notes

  1. Ofir Hakim, Wolfgang Resch, Arito Yamane, Michel C. Nussenzweig and Rafael Casellas: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Ofir Hakim, Ty C. Voss & Gordon L. Hager
  2. Genomics & Immunity, NIAMS, NCI, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Wolfgang Resch, Arito Yamane, Kyong-Rim Kieffer-Kwon, Camilo Ansarah-Sobrinho, Genqing Liang, Jesse Cobell, Hirotaka Nakahashi & Rafael Casellas
  3. Laboratory of Molecular Immunology, The Rockefeller University, New York, 10065, New York, USA
    Isaac Klein, Mila Jankovic, Thiago Oliveira, Anne Bothmer, Davide F. Robbiani & Michel C. Nussenzweig
  4. Departmento of Genetics, Medical School of Ribeirao Preto/USP, 8 National Institute of Science and Technology for Stem Cells and Cell Therapy and Center for Cell-based Therapy, Ribeirao Preto, SP 14051-140, Brazil,
    Thiago Oliveira
  5. Biodata Mining and Discovery, NIAMS, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Ewy Mathe
  6. Laboratory of Genome Integrity, NCI, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Andre Nussenzweig
  7. Howard Hughes Medical Institute, The Rockefeller University, New York, 10065, New York, USA
    Michel C. Nussenzweig
  8. Center of Cancer Research, NCI, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Rafael Casellas

Authors

  1. Ofir Hakim
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  2. Wolfgang Resch
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  3. Arito Yamane
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  4. Isaac Klein
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  5. Kyong-Rim Kieffer-Kwon
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  6. Mila Jankovic
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  7. Thiago Oliveira
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  8. Anne Bothmer
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  9. Ty C. Voss
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  10. Camilo Ansarah-Sobrinho
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  11. Ewy Mathe
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  12. Genqing Liang
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  13. Jesse Cobell
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  14. Hirotaka Nakahashi
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  15. Davide F. Robbiani
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  16. Andre Nussenzweig
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  17. Gordon L. Hager
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  18. Michel C. Nussenzweig
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  19. Rafael Casellas
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Contributions

R.C., O.H., G.L.H. and M.C.N. planned studies and interpreted data. Experiments were performed as follows: O.H. and C.A.-S., 4C-seq and FISH; A.Y., RPA-seq; I.K., A.B., D.F.R. and M.J., TC-seq; W.R., E.M. and T.O., bioinformatics; K.-R.K.-K., T.C.V., H.N. and J.C., FISH; G.L. and H.N., hypermutation; A.N., 53BP1 expertise; M.C.N. and R.C. wrote the manuscript.

Corresponding authors

Correspondence toMichel C. Nussenzweig or Rafael Casellas.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information This file contains Supplementary Figures 1-12 with legends and Supplementary Tables 1-4, and 6-9 (see separate files for Supplementary Tables 5 and 6). (PDF 5674 kb)

Supplementary Table 5

This table shows Igh or c-myc nuclear interactions with Ref-Seq genes as provided by 4C-Seq. (PDF 13075 kb)

Supplementary Table 6

This table shows RPA signals per gene. (PDF 9267 kb)

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Hakim, O., Resch, W., Yamane, A. et al. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes.Nature 484, 69–74 (2012). https://doi.org/10.1038/nature10909

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Editorial Summary

DNA breakage and translocation

Translocations — events that swap the arms of two different chromosomes — are found in many cancers. It is thought that they occur when the interaction sites become close in nuclear space. Rafael Casellas and colleagues have now done a genome-wide analysis to determine the contribution of DNA breaks to the formation of random and recurrent translocations. Whereas random translocations are found to be highly sensitive to nuclear interactions between chromosomes, the frequency of recurrent translocations, including those involved in human cancer, is proportional to the amount of DNA damage at these highly utilized sites.