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Cell. 2011 Sep 30;147(1):107-19. doi: 10.1016/j.cell.2011.07.049.

Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells.

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Howard Hughes Medical Institute, Immune Disease Institute, Program in Cellular and Molecular Medicine, Children's Hospital Boston and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Erratum in

  • Cell. 2011 Dec 23;147(7):1640.


Whereas chromosomal translocations are common pathogenetic events in cancer, mechanisms that promote them are poorly understood. To elucidate translocation mechanisms in mammalian cells, we developed high-throughput, genome-wide translocation sequencing (HTGTS). We employed HTGTS to identify tens of thousands of independent translocation junctions involving fixed I-SceI meganuclease-generated DNA double-strand breaks (DSBs) within the c-myc oncogene or IgH locus of B lymphocytes induced for activation-induced cytidine deaminase (AID)-dependent IgH class switching. DSBs translocated widely across the genome but were preferentially targeted to transcribed chromosomal regions. Additionally, numerous AID-dependent and AID-independent hot spots were targeted, with the latter comprising mainly cryptic I-SceI targets. Comparison of translocation junctions with genome-wide nuclear run-ons revealed a marked association between transcription start sites and translocation targeting. The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics.

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