The Journal of Experimental Medicine
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Published online 12 May 2003 doi:10.1084/jem.20022190
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© Rockefeller University Press, 0022-1007/2003/5/1377 $5.00
The Journal of Experimental Medicine, Volume 197, Number 10, 1377-1383

Brief Definitive Report

Mlh1 Can Function in Antibody Class Switch Recombination Independently of Msh2

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 01655-0122

Address correspondence to J. Stavnezer, Department 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: 508-856-5920; E-mail: janet.stavnezer{at}umassmed.edu

Mismatch repair proteins participate in antibody class switch recombination, although their roles are unknown. Previous nucleotide sequence analyses of switch recombination junctions indicated that the roles of Msh2 and the MutL homologues, Mlh1 and Pms2, differ. We now asked if Msh2 and Mlh1 function in the same pathway during switch recombination. Splenic B cells from mice deficient in both these proteins were induced to undergo switching in culture. The frequency of switching is reduced, similarly to that of B cells singly deficient in Msh2 or Mlh1. However, the nucleotide sequences of the Sµ-S{gamma}3 junctions resemble junctions from Mlh1- but not from Msh2-deficient cells, suggesting Mlh1 functions either independently of or before Msh2. The substitution mutations within S regions that are known to accompany switch recombination are increased in Msh2- and Mlh1 single-deficient cells and further increased in the double-deficient cells, again suggesting these proteins function independently in class switch recombination. The finding that MMR functions to reduce mutations in switch regions is unexpected since MMR proteins have been shown to contribute to somatic hypermutation of antibody variable region genes.

Key Words: B cells • immunoglobulin isotypes • mismatch repair • switch region mutations • switch junctions


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