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.