Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells
Department of Microbiology and Physiological Systems
Medical Subject Headings
Amino Acid Motifs; Animals; B-Lymphocytes; Binding Sites; Carrier Proteins; Cytidine Deaminase; *DNA Breaks, Double-Stranded; Genes, myc; Immunoglobulin Class Switching; Lymphocyte Activation; Mice; Nuclear Proteins; Repetitive Sequences, Nucleic Acid
Genetics and Genomics | Immunology and Infectious Disease
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.
Staszewski, Ori; Baker, Richard E.; Ucher, Anna J.; Martier, Raygene; Stavnezer, Janet; and Guikema, Jeroen E. J., "Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells" (2011). Microbiology and Physiological Systems Publications and Presentations. 7.