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DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes


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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Figure 1: Characterization of the Igh, Myc and Mycn interactomes in B lymphocytes.
Figure 2: Genomic distribution of AID-independent translocations correlates with nuclear contact profiles.
Figure 3: Lack of correlation between translocation hotspots and nuclear architecture.
Figure 4: Genome-wide map of AID-mediated DNA damage.
Figure 5: AID activity predicts the location and frequency of targeted chromosomal translocations.

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Sequence Read Archive

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


  1. 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 

  2. Nussenzweig, A. & Nussenzweig, M. C. Origin of chromosomal translocations in lymphoid cancer. Cell 141, 27–38 (2010)

    Article  CAS  Google Scholar 

  3. Tsai, A. G. et al. Human chromosomal translocations at CpG sites and a theoretical basis for their lineage and stage specificity. Cell 135, 1130–1142 (2008)

    Article  CAS  Google Scholar 

  4. Zhang, Y. et al. The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. Adv. Immunol. 106, 93–133 (2010)

    Article  CAS  Google Scholar 

  5. Cremer, T. & Cremer, M. Chromosome territories. Cold Spring Harb. Perspect. Biol. 2, a003889 (2010)

    Article  Google Scholar 

  6. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009)

    Article  ADS  CAS  Google Scholar 

  7. Hakim, O., Sung, M. H. & Hager, G. L. 3D shortcuts to gene regulation. Curr. Opin. Cell Biol. 22, 305–313 (2010)

    Article  CAS  Google Scholar 

  8. Chakalova, L. & Fraser, P. Organization of transcription. Cold Spring Harb. Perspect. Biol. 2, a000729 (2010)

    Article  Google Scholar 

  9. Klein, I. A. et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147, 95–106 (2011)

    Article  CAS  Google Scholar 

  10. Chiarle, R. et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147, 107–119 (2011)

    Article  CAS  Google Scholar 

  11. Simonis, M. et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nature Genet. 38, 1348–1354 (2006)

    Article  CAS  Google Scholar 

  12. Robbiani, D. F. et al. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol. Cell 36, 631–641 (2009)

    Article  CAS  Google Scholar 

  13. Yamane, A. et al. Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes. Nature Immunol. 12, 62–69 (2011)

    Article  CAS  Google Scholar 

  14. Hakim, O. et al. Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements. Genome Res. 21, 697–706 (2011)

    Article  CAS  Google Scholar 

  15. Osborne, C. S. et al. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh. PLoS Biol. 5, e192 (2007)

    Article  Google Scholar 

  16. Roix, J. J., McQueen, P. G., Munson, P. J., Parada, L. A. & Misteli, T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nature Genet. 34, 287–291 (2003)

    Article  CAS  Google Scholar 

  17. Parada, L. A., McQueen, P. G. & Misteli, T. Tissue-specific spatial organization of genomes. Genome Biol. 5, R44 (2004)

    Article  Google Scholar 

  18. Kuchen, S. et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 32, 828–839 (2010)

    Article  CAS  Google Scholar 

  19. Brown, K. E., Baxter, J., Graf, D., Merkenschlager, M. & Fisher, A. G. Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol. Cell 3, 207–217 (1999)

    Article  CAS  Google Scholar 

  20. Meaburn, K. J. & Misteli, T. Cell biology: chromosome territories. Nature 445, 379–381 (2007)

    Article  ADS  CAS  Google Scholar 

  21. Vuong, B. Q. et al. Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination. Nature Immunol. 10, 420–426 (2009)

    Article  CAS  Google Scholar 

  22. Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010)

    Article  CAS  Google Scholar 

  23. Bothmer, A. et al. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J. Exp. Med. 207, 855–865 (2010)

    Article  CAS  Google Scholar 

  24. Wang, J. H. et al. Mechanisms promoting translocations in editing and switching peripheral B cells. Nature 460, 231–236 (2009)

    Article  ADS  CAS  Google Scholar 

  25. Robbiani, D. F. et al. AID is required for the chromosomal translocations in c-myc that lead to c-myc/IgH translocations. Cell 135, 1028–1038 (2008)

    Article  CAS  Google Scholar 

  26. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  Google Scholar 

  27. Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010)

    Article  CAS  Google Scholar 

  28. Zang, C. et al. A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25, 1952–1958 (2009)

    Article  CAS  Google Scholar 

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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 (, and the resources of NCI’s High-Throughput Imaging Facility.

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Authors and Affiliations



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 to Michel C. Nussenzweig or Rafael Casellas.

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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).

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