DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes |
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Authors: | Hakim Ofir Resch Wolfgang Yamane Arito Klein Isaac Kieffer-Kwon Kyong-Rim Jankovic Mila Oliveira Thiago Bothmer Anne Voss Ty C Ansarah-Sobrinho Camilo Mathe Ewy Liang Genqing Cobell Jesse Nakahashi Hirotaka Robbiani Davide F Nussenzweig Andre Hager Gordon L Nussenzweig Michel C Casellas Rafael |
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Affiliation: | Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA. |
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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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