Mus musculus Circular chromosome conformation capture (4C) and RPA ChIP-Seq from mouse B cells

Recurrent chromosomal translocations produce a large number of hematopoietic and solid tumors. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners. Although proximity in cis and transcription facilitate rearrangements, the relative contributions of nuclear interaction and DNA damage to random versus recurrent translocations have not been measured directly or on a large scale. Here we examine the role of global nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or c-myc and all other genes is directly related to their contact frequency. In contrast, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA double strand break formation, as measured by accumulation of replication protein A (RPA) at the site of damage. Our findings demonstrate that non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent chromosomal translocations, including those driving B cell malignancies.