Targeting of somatic hypermutation

Key Points The targeting of somatic hypermutation (SHM) occurs at two distinct levels. 'Global' targeting refers to the fact that rearranged immunoglobulin variable regions are the primary substrate for SHM. By contrast, 'local' targeting refers to the observation that mutations are confined to a 1–2 kilobase (kb) region in the variable region. SHM was once thought to target rearranged immunoglobulin variable regions exclusively. It has now been shown to occasionally mistarget oncogenes, including B-cell lymphoma 6 ( BCL6 ) and CD95 . Activation-induced cytidine deaminase (AID) is required for SHM, but the substrate specificity of AID cannot explain the targeting of SHM. DNA-repair processes are typically error-free but during SHM they are likely to be perturbed and rendered error-prone. The resulting error-prone repair pathway(s) must be targeted to rearranged immunoglobulin variable regions. Studies using κ-light chain (Igκ)-like transgenes showed that immunoglobulin enhancer regions are required for targeting SHM to variable regions. More recently, however, studies of endogenous immunoglobulin loci have called into question both the role of immunoglobulin enhancers in SHM and the usefulness of traditional transgenes in dissecting the molecular mechanism of targeting. Conventional histone modifications do not seem to have a direct role in targeting SHM. By contrast, the modification H2B Ser14P (histone H2B phosphorylated on serine residue 14) is spatially and temporally correlated with SHM. Recent insights and the development of new experimental strategies should continue to determine the mechanisms by which SHM is targeted to immunologlobulin loci, as well as the reason that this reaction is occasionally mistargeted to oncogenes. Somatic hypermutation (SHM) introduces mutations in the variable region of immunoglobulin genes, to generate high-affinity B-cell antigen receptors. But, as discussed in this Review, how SHM is targeted to immunoglobulin genes is a subject of intense research and debate. Somatic hypermutation (SHM) introduces mutations in the variable region of immunoglobulin genes at a rate of ∼10 −3 mutations per base pair per cell division, which is 10 6 -fold higher than the spontaneous mutation rate in somatic cells. To ensure genomic integrity, SHM needs to be targeted specifically to immunoglobulin genes. The rare mistargeting of SHM can result in mutations and translocations in oncogenes, and is thought to contribute to the development