Journal
CELL
Volume 147, Issue 1, Pages 107-119Publisher
CELL PRESS
DOI: 10.1016/j.cell.2011.07.049
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Funding
- NIH [5P01CA92625, AI070837, 5T32CA070083-13]
- Leukemia and Lymphoma Society of America (LLS)
- AIRC [ERC-2009-StG, 242965]
- V Foundation
- CRI postdoctoral fellowship
- European Research Council (ERC) [242965] Funding Source: European Research Council (ERC)
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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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