Molecular aspects of heavy-chain class switching

Abstract

Ig heavy chain class switching results from recombination that specifically joins together tandemly repeated sequences called S-regions. S-regions are located 5' of every CH gene except C delta. Recombination between S mu and a downstream S-region results in the juxtaposition of the rearranged variable region genes with C gamma, C epsilon, or C alpha genes and expression of the new isotype. Switch recombination is probably mediated by specific recombinase(s) that may be involved in other types of Ig-gene recombination. The efficiency and regulation of class-switch recombination is influenced by a number of factors, both structural and functional. Structurally, S-regions are all composed of tandemly repeated sequences that contain common pentamer sequences, but they differ in their length and their degree of sequence similarity with S mu. The mechanism of switching appears to be influenced by the accessibility of the S-region to recombinase(s). The conformational changes that result in accessibility are unknown but are correlated with transcription and hypomethylation of DNA near S-regions. Torsional stress resulting from progression of RNA polymerase through a GC-rich S-region could serve to further distort the DNA conformation and open the duplex, thus making it available for DNA strand invasion and recombinase activity. Although the mechanistic events of S-S recombination remain to be elucidated, switching is clearly influenced by protein mediators (mitogens and interleukins) which induce differential transcription of S regions.