DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

Ofir Hakim, Wolfgang Resch, Arito Yamane, Isaac Klein, Kyong Rim Kieffer-Kwon, Mila Jankovic, Thiago Oliveira, Anne Bothmer, Ty C. Voss, Camilo Ansarah-Sobrinho, Ewy Mathe, Genqing Liang, Jesse Cobell, Hirotaka Nakahashi, Davide F. Robbiani, Andre Nussenzweig, Gordon L. Hager, Michel C. Nussenzweig, Rafael Casellas

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174 Scopus citations


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.

Original languageEnglish
Pages (from-to)69-74
Number of pages6
Issue number7392
StatePublished - 5 Apr 2012
Externally publishedYes

Bibliographical note

Funding Information:
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 a grant from the Starr Foundation to M.C.N., by NIH grantnumberAI037526toM.C.N.and the IntramuralResearchProgram ofNIAMS 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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