MMR proteins in eukaryotes fall into two classes: (i) the MutS homologs (Msh1–6) which recognize DNA mismatches, loops, and other distortions, and (ii) the MutL homologs (Pms1, Pms2, and Mlh1 in mammals) which bind to MutS homologs bound to DNA (for a review, see reference 12). Recently, mismatch repair (MMR) proteins have been shown to be involved in both CSR and somatic hypermutation. The data indicate that MMR proteins are directly involved in class switching and that the role of Msh2 differs from that of Mlh1 and Pms2. By contrast, 23% of junctions from Mlh1- and Pms2-deficient cells occurred at unusually long stretches of microhomology. Sequences of switch junctions from Msh2-deficient cells showed decreased lengths of microhomology between Sμ and Sγ3 relative to junctions from wild-type cells and an increase in insertions, i.e., nucleotides which do not appear to be derived from either the Sμ or Sγ3 parental sequence. The data demonstrate clear differences in the sequences of switch junctions in wild-type B cells in comparison with Msh2-, Mlh1-, and Pms2-deficient B cells. To assess the role of MMR in switching we examined the nucleotide sequences of Sμ-Sγ3 recombination junctions in splenic B cells induced in culture to switch to IgG3. The deficit is not accompanied by any reduction in cell viability or alterations in the cell cycle in B cells cultured in vitro. B cells from mice deficient in mismatch repair (MMR) proteins show decreased ability to undergo class switch recombination in vitro and in vivo.
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