Enhancers of hypermutation

Abstract

 Hypermutation at the immunoglobulin (Ig) loci increases the mutation rate more than 10⁵-fold over the normal, spontaneous rate. We studied two kinds of cis-acting elements – 3′ enhancers and promoters – in a system in which a gene encoding the μ heavy (H) chain (Igm) is transfected in vitro into a cell line with an active Ig mutator. A construct containing a rearranged Igm gene requires the 3′H enhancer for hypermutation at a rate comparable with the one at the endogenous gene segment encoding the H chain variable region (V). Without the 3′ enhancer, the basal mutational activity is much lower, but still higher than the normal, spontaneous mutation rate. Replacement of the 3′H enhancer by atopic elements of similar function also supports full hypermutation. Even though these 3′ elements are defined as transcriptional enhancers, they do not seem to increase hypermutation via an increase in the rate of transcription. Replacement of the endogenous promoter by the tk promoter slightly increases hypermutability of the construct; thus, no specific sequences in the Ig promoter are likely to target hypermutation.