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AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations.

Author(s): Davide Robbiani, Samuel Bunting, Niklas Feldhahn, Anne Bothmer, Jordi Camps, Stephanie Deroubaix, Kevin M. McBride, Isaac A. Klein, Gary Stone, Thomas Eisenreich, Thomas Ried, André Nussenzweig, Michel Nussenzweig

Publication date: 2009-11-25

Journal: Molecular Cell

Keywords: Animals, B-Lymphocytes, cytology, enzymology, Cell Differentiation, genetics, Cells, Cultured, Chromosomal Instability, Chromosomes, Mammalian, Cytidine Deaminase, metabolism, DNA Breaks, Double-Stranded, DNA Damage, Genes, Immunoglobulin, Humans, Immunoglobulin Class Switching, Karyotyping, Lymphoma, B-Cell, pathology, Mice, Mice, Transgenic, MicroRNAs, Phenotype, Proto-Oncogene Proteins c-myc, Somatic Hypermutation, Immunoglobulin, Translocation, Genetic, Tumor Suppressor Protein p53, deficiency

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Abstract

Cancer-initiating translocations such as those associated with lymphomas require the formation of paired DNA double-strand breaks (DSBs). Activation-induced cytidine deaminase (AID) produces widespread somatic mutation in mature B cells; however, the extent of "off-target" DSB formation and its role in translocation-associated malignancy is unknown. Here, we show that deregulated expression of AID causes widespread genome instability, which alone is insufficient to induce B cell lymphoma; transformation requires concomitant loss of the tumor suppressor p53. Mature B cell lymphomas arising as a result of deregulated AID expression are phenotypically diverse and harbor clonal reciprocal translocations involving a group of Immunoglobulin (Ig) and non-Ig genes that are direct targets of AID. This group includes miR-142, a previously unknown micro-RNA target that is translocated in human B cell malignancy. We conclude that AID produces DSBs throughout the genome, which can lead to lymphoma-associated chromosome translocations in mature B cells.