Secret sharers in the immune system: a novel RNA editing activity links switch recombination and somatic hypermutation

We have become accustomed to the notion that the immune system tampers with the genome. First, rearrangement of V,D, and J gene segments creates the antigen receptor variable regions. V(D)J recombination depends on the site-specific recombination proteins, RAG1 and RAG2, and occurs early in development of both B cells and T cells (reviewed in [1,2]). Subsequent encounter with antigen stimulates two additional and distinct processes that modify the genomes of B cells, but not T cells: class switch recombination and somatic hypermutation (see Figure 1). Switch recombination joins an expressed heavy chain variable (VDJ) region to a new downstream constant (C) region, changing the antigen clearance properties of an antibody without altering its specificity for antigen (reviewed in [3,4]). Switch recombination is a region-specific recombination process that deletes many kilobases of DNA and produces heterogeneous recombination junctions. Circles containing the deleted DNA can be found in B cells that have recently completed switch recombination, suggesting that regions targeted for recombination can synapse to form a recombination intermediate, which is then cleaved and religated. In contrast, somatic hypermutation is a targeted mutation process resulting in single nucleotide substitutions. These single base changes occur in an expressed heavy or light chain variable region, providing the genetic raw material for subsequent selection of clones producing high-affinity antibodies (reviewed in [5]). The currently prevailing model for hypermutation envisions an initial DNA break that is repaired by an error-prone polymerase, but no specific nuclease or polymerase has as yet been conclusively linked to somatic hypermutation.Recent results, appearing in the September 1 issue of Cell [6,7], now show that the immune system's tampering is not limited to DNA, but that RNA editing is an additional tool in its bag of tricks. These exciting results have many implications. First, they