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Genome-wide analysis of AID activity and AID-mediated translocations in B lymphocytes

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B lymphocytes are particularly prone to cancer-promoting translocations as a result of activation-induced cytidine deaminase (AID) expression. This enzyme normally diversifies antibody genes by initiating immunoglobulin (Ig) class switch recombination and somatic hypermutation. Although AID has a strong preference for targeting the Ig loci, it also mutates non-Ig genes, including Bcl6, Pax5, miR142, Pim1, and c-myc oncogenes. Of these, c-myc is the only one conclusively shown to undergo chromosomal translocations because of AID . Yet, it has been estimated that up to 5% of activated primary B lymphocytes carry Ig fusions to a large number of unidentified partners1. Consistent with this idea, we recently characterized thousands of potential AID targets in the B cell genome by means of ChIP-Seq technology2. We showed that AID is recruited to promoter proximal sequences of these genes by interacting with Spt53, an RNA polymerase stalling factor. However, whether any of these new targets undergoes AID -mediated lesions or whether they are substrates of chromosomal translocations is unclear. To directly answer these questions we have developed two new genome-wide strategies that comprehensively map AID -dependent DNA breaks, rearrangements, and Ig gene translocations in B lymphocytes. In contrast to the large number of AID recruiting genes, our studies uncover ~150 targets that are frequently associated with DNA lesions and fuse to recombining Ig loci upon B cell activation. How chromosome position, epigenetic marks, and gene transcription contribute to these chromosomal rearrangements will be discussed.

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