Activation-Induced Cytidine Deaminase Induces Reproducible DNA Breaks at Many Non-Ig Loci in Activated B Cells

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655-0122, USA.
Molecular cell (Impact Factor: 14.02). 01/2011; 41(2):232-42. DOI: 10.1016/j.molcel.2011.01.007
Source: PubMed


After immunization or infection, activation-induced cytidine deaminase (AID) initiates diversification of immunoglobulin (Ig) genes in B cells, introducing mutations within the antigen-binding V regions (somatic hypermutation, SHM) and double-strand DNA breaks (DSBs) into switch (S) regions, leading to antibody class switch recombination (CSR). We asked if, during B cell activation, AID also induces DNA breaks at genes other than IgH genes. Using a nonbiased genome-wide approach, we have identified hundreds of reproducible, AID-dependent DSBs in mouse splenic B cells shortly after induction of CSR in culture. Most interestingly, AID induces DSBs at sites syntenic with sites of translocations, deletions, and amplifications found in human B cell lymphomas, including within the oncogene B cell lymphoma11a (bcl11a)/evi9. Unlike AID-induced DSBs in Ig genes, genome-wide AID-dependent DSBs are not restricted to transcribed regions and frequently occur within repeated sequence elements, including CA repeats, non-CA tandem repeats, and SINEs.

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Available from: Janet Stavnezer, Feb 28, 2014
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    • "Currently, it is not known whether the ncMMR mutagenic activity is engaged exclusively at AID deaminated sites in the immunoglobulin locus. AID may act on many non-Ig genes (Liu et al., 2008; Chiarle et al., 2011; Klein et al., 2011; Staszewski et al., 2011; Fear, 2013) and spontaneous deamination of cytosine to uracil is also a frequent event (∼200 per mammalian genome per day; Kavli et al., 2007). Therefore, lesions that can be recognized by MMR are not locus specific and MMR mutagenic activities may be more frequent than anticipated. "
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    • "It has been reported that AID instigates formation of widespread DSBs throughout the genome in activated B cells, albeit at significantly lower levels than that at the IgH locus (133–136). Such off-target DSBs at non-IgH loci are the major underlying lesions contributing to translocations between IgH and non-IgH loci (such as c-Myc) in B cells and are largely responsible for the ontogeny of a large number of B cell lymphomas in humans (21). "
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    • "AID also induces mutations and breaks in numerous non-Ig genes, many of which (but not all) are transcribed in B cells, and many of which overlap with translocation or recombination sites found in B cell lymphomas or correspond to repetitive DNA sequences. [101,102]. Studies of B cell malignancies since the early 1980s also identified a number of translocations linking oncogenes such as c-MYC, c-MAF, CYCLIN D1, and BCL2 to breakpoints located within Ig loci. Some of these events were recurrently identified as the clonal driving forces of lymphomagenesis. "
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    ABSTRACT: Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.
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