CIS-ACTING SEQUENCES THAT AFFECT SOMATIC HYPERMUTATION OF IG GENES

We review our studies on the mechanism of somatic hypermutation of imm unoglobulin genes. Most experiments were carried out using Ig transgen es. We showed in these experiments that all required cis-acting elemen ts are present within the 10-16 kb of a transgene. Only the Ig variabl e region and its proximate flanks are mutated, not the constant region . Several Ig gene enhancers are permissive for somatic mutation. Assoc iation of the enhancer with its natural Ig promoter is not necessary. Ho Never, the mutation process seems specific for Ig genes. No mutatio ns were found in housekeeping genes from cells with high levels of som atic hypermutation of their Ig genes. The Ig enhancers may provide the Ig gene specificity. An exception may be the BCL6 gene, which was mut ated in human but not in mouse B cells. Transcription of a region is r equired for its mutability. When the transcriptional promoter located upstream of the variable region is duplicated upstream of the constant region, this region also becomes mutable. This suggests a model in wh ich a mutator factor associates with the RNA polymerase at the promote r, travels with the polymerase during elongation, and causes mutations during polymerase pausing. The DNA repair systems, nucleotide excisio n repair and DNA mismatch repair, are nor required. Our recent data wi th an artificial substrate of somatic mutation suggest that pausing ma y be due to secondary structure of the DNA or nascent RNA, and the spe cific mutations to preferences of the mutator Factor.