The Journal of Experimental Medicine
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Published 4 February 2002. doi:10.1084/jem.20011877
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© Rockefeller University Press, 0022-1007/2002/2/367/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 3, February 4, 2002 367-373

Brief Definitive Report

Role for Mismatch Repair Proteins Msh2, Mlh1, and Pms2 in Immunoglobulin Class Switching Shown by Sequence Analysis of Recombination Junctions

Carol E. Schrader, Joycelyn Vardo and Janet Stavnezer

Department of Molecular Genetics and Microbiology and Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655

Address correspondence to Janet Stavnezer, Dept. of Molecular Genetics and Microbiology and Program in Immunology and Virology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655-0122. Phone: 508-856-4100; Fax: 508-856-1789; E-mail: janet.stavnezer{at}umassmed.edu

B cells from mice deficient in mismatch repair (MMR) proteins show decreased ability to undergo class switch recombination in vitro and in vivo. The deficit is not accompanied by any reduction in cell viability or alterations in the cell cycle in B cells cultured in vitro. To assess the role of MMR in switching we examined the nucleotide sequences of Sµ-S{gamma}3 recombination junctions in splenic B cells induced in culture to switch to IgG3. 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. Sequences of switch junctions from Msh2-deficient cells showed decreased lengths of microhomology between Sµ and S{gamma}3 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 S{gamma}3 parental sequence. By contrast, 23% of junctions from Mlh1- and Pms2-deficient cells occurred at unusually long stretches of microhomology. 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.

Key Words: splenic B cells • DNA recombination • DNA repair • antibody heavy chain isotypes • mismatch repair


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