Mutations occur in the Ig Smu region but rarely in Sgamma regions prior to class switch recombination
Department of Molecular Genetics and Microbiology
Animals; B-Lymphocytes; Base Composition; Base Sequence; DNA; DNA Nucleotidylexotransferase; DNA Repair; *DNA-Binding Proteins; *Immunoglobulin Switch Region; Lymphocyte Activation; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; MutS Homolog 2 Protein; *Mutation; Proto-Oncogene Proteins; Recombinant Proteins; *Recombination, Genetic
Life Sciences | Medicine and Health Sciences | Women's Studies
Nucleotide substitutions are found in recombined Ig switch (S) regions and also in unrecombined (germline, GL) Smicro segments in activated splenic B cells. Herein we examine whether mutations are also introduced into the downstream acceptor S regions prior to switch recombination, but find very few mutations in GL Sgamma3 and Sgamma1 regions in activated B cells. These data suggest that switch recombination initiates in the Smicro segment and secondarily involves the downstream acceptor S region. Furthermore, the pattern and specificity of mutations in GL and recombined Smicro segments differ, suggesting different repair mechanisms. Mutations in recombined Smicro regions show a strong bias toward G/C base pairs and WRCY/RGYW hotspots, whereas mutations introduced into the GL Smicro do not. Additionally, induction conditions affect mutation specificity within the GL Smicro segment. Mutations are most frequent near the S-S junctions and decrease rapidly with distance from the junction. Finally, we find that mice expressing a transgene for terminal deoxynucleotidyl transferase (TdT) have nucleotide insertions at S-S junctions, indicating that the recombining DNA ends are accessible to end-processing enzyme activities.
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Citation: EMBO J. 2003 Nov 3;22(21):5893-903. Link to article on publisher's site