Towards an understanding of somatic hypermutation.
How germinal center (GC) B cells diversify their rearranged immunoglobulin genes by somatic hypermutation is unknown. However, the GC-specific activation-induced cytidine deaminase has been identified as a key factor controlling two central GC-specific events: somatic hypermutation and class-switch recombination of immunoglobulin genes. This factor may function as a catalytic subunit of an RNA-editing complex or, more directly, on DNA as a deoxy-cytidine deaminase in the hypermutation domain and class-switch region. Deamination of deoxy-cytidines on both strands may result in staggered DNA double-strand breaks (DSBs) that, in the hypermutation domain, become processed by member(s) of newly identified error-prone DNA polymerases. Direct evidence for DSBs in hot-spots of hypermutating immunoglobulin genes has been provided, implicating DSBs as reaction intermediates of an error-prone DSB-repair pathway acting specifically in GC B cells. These recent findings are key to the identification of the hypermutation mechanism.
Jacobs
H
H
Basel Institute for Immunology, Grenzacherstrasse 487, CH-4005, Basel, Switzerland. Jacobs@BII.CH
Bross
L
L
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D020137:Base Pair Mismatch / Q000235:genetics; D003564:Cytidine Deaminase / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005803:Genes, Immunoglobulin / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
D003564:Cytidine Deaminase