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DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

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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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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Primary accessions

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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Authors

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 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). https://doi.org/10.1038/nature10909

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