Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells.
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.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655-0122, USA.
Ori
O
Staszewski
Richard E
RE
Baker
Anna J
AJ
Ucher
Raygene
R
Martier
Janet
J
Stavnezer
Jeroen E J
JE
Guikema
D020816:Amino Acid Motifs; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology*; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry; D003564:Cytidine Deaminase / Q000378:metabolism / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins; D016259:Genes, myc; D017578:Immunoglobulin Class Switching; D008213:Lymphocyte Activation; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry; D012091:Repetitive Sequences, Nucleic Acid; D012097:Repressor Proteins
C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D003564:Cytidine Deaminase
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