The Sμ tandem repeat region is critical for Ig isotype switching in the absence of Msh2

Deficiencies of the Msh2 protein or the Sμ tandem repeat (SμTR) sequences each reduce isotype switching in mice by about 2- to 3-fold. We find that switching in mice deficient for both Msh2 and SμTR is nearly ablated. We propose that the SμTR provides closely spaced cleavage sites that can undergo switch recombination independent of Msh2, whereas cleavages in sequences flanking the SμTR require Msh2 processing to allow recombinational joining. We also find that changes in Sμ sequences alter the focus of switch junctions within Sγ sequences, indicating that sequences of switch regions act together in the choice of switch recombination junctions. These findings help to explain the conservation of tandemly repeated switch regions associated with heavy chain constant genes in species capable of switching.