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 () and Rafael Casellas ()
Additional contact information
Ofir Hakim: Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health
Wolfgang Resch: Genomics & Immunity, NIAMS, NCI, National Institutes of Health
Arito Yamane: Genomics & Immunity, NIAMS, NCI, National Institutes of Health
Isaac Klein: Laboratory of Molecular Immunology, The Rockefeller University
Kyong-Rim Kieffer-Kwon: Genomics & Immunity, NIAMS, NCI, National Institutes of Health
Mila Jankovic: Laboratory of Molecular Immunology, The Rockefeller University
Thiago Oliveira: Laboratory of Molecular Immunology, The Rockefeller University
Anne Bothmer: Laboratory of Molecular Immunology, The Rockefeller University
Ty C. Voss: Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health
Camilo Ansarah-Sobrinho: Genomics & Immunity, NIAMS, NCI, National Institutes of Health
Ewy Mathe: Biodata Mining and Discovery, NIAMS, National Institutes of Health
Genqing Liang: Genomics & Immunity, NIAMS, NCI, National Institutes of Health
Jesse Cobell: Genomics & Immunity, NIAMS, NCI, National Institutes of Health
Hirotaka Nakahashi: Genomics & Immunity, NIAMS, NCI, National Institutes of Health
Davide F. Robbiani: Laboratory of Molecular Immunology, The Rockefeller University
Andre Nussenzweig: Laboratory of Genome Integrity, NCI, National Institutes of Health
Gordon L. Hager: Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health
Michel C. Nussenzweig: Laboratory of Molecular Immunology, The Rockefeller University
Rafael Casellas: Genomics & Immunity, NIAMS, NCI, National Institutes of Health

Nature, 2012, vol. 484, issue 7392, 69-74

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature10909

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