High levels of AID cause strand bias of mutations at A versus T in Burkitt's lymphoma cells

• Published in: Molecular immunology 2013-07, Vol.54 (3-4), p.397-402
• Main Authors: Kano, Chie, Wang, Ji-Yang
• Format: Article
• Language: English
• Subjects: A:T mutation; Activation-induced cytidine deaminase; B-Lymphocytes - metabolism; B-Lymphocytes - physiology; Base Sequence; Burkitt Lymphoma - enzymology; Burkitt Lymphoma - genetics; Burkitt Lymphoma - immunology; Burkitt Lymphoma - metabolism; Cell Line; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Genes, Immunoglobulin; Germinal Center - metabolism; Germinal Center - physiology; Germinal center B cells; Humans; Immunoglobulin gene hypermutation; Molecular Sequence Data; Mutagenesis; Mutation; Proto-Oncogene Proteins c-bcl-6; Strand bias
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2013.01.005

► Ig gene hypermutation occurs more frequently at A versus T (A/T bias) on the non-transcribed strand of V genes. ► We found that the generation of A/T bias requires high levels of AID. ► These results explain why A/T bias is found only in the highly mutated V genes but not in the less mutated switch region. ► Our results identify a clue to the strand bias and provide an in vitro model to elucidate this unsolved mystery. Ig gene somatic hypermutation in the germinal center (GC) B cells occurs at C and G at roughly the same frequency. In contrast, there is a 2-fold increase of mutations at A relative to T on the non-transcribed strand of the V genes but it is unclear what triggers such strand bias. Using an efficient mutagenesis system that recapitulates characteristic features of Ig gene hypermutation in the GC B cells, we found that low levels of AID induced similar frequency of mutations at A and T. However, high levels of AID specifically increased mutations at A, but not T, leading to strand bias. These results explain why strand bias of A:T mutations is observed only in the highly mutated V genes but not in the less mutated switch region or the BCL-6 gene. High levels of AID also increased the proportion of transversions at G relative to transversions at C. Our results identify a clue to the strand bias of A:T mutations and provide an in vitro model to elucidate this unsolved mystery in the hypermutation field.