The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published 6 July 2004. doi:10.1084/jem.20040691
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 1, 61-68
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A Role for Msh6 But Not Msh3 in Somatic Hypermutation and Class Switch Recombination

Stella A. Martomo, William W. Yang, and Patricia J. Gearhart

Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

Address correspondence to Patricia J. Gearhart, Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: (410) 558-8561; Fax: (410) 558-8157; email: gearhartp{at}grc.nia.nih.gov

Somatic hypermutation is initiated by activation-induced cytidine deaminase (AID), and occurs in several kilobases of DNA around rearranged immunoglobulin variable (V) genes and switch (S) sites before constant genes. AID deaminates cytosine to uracil, which can produce mutations of C:G nucleotide pairs, and the mismatch repair protein Msh2 participates in generating substitutions of downstream A:T pairs. Msh2 is always found as a heterodimer with either Msh3 or Msh6, so it is important to know which one is involved. Therefore, we sequenced V and S regions from Msh3- and Msh6-deficient mice and compared mutations to those from wild-type mice. Msh6-deficient mice had fewer substitutions of A and T bases in both regions and reduced heavy chain class switching, whereas Msh3-deficient mice had normal antibody responses. This establishes a role for the Msh2-Msh6 heterodimer in hypermutation and switch recombination. When the positions of mutation were mapped, several focused peaks were found in Msh6–/– clones, whereas mutations were dispersed in Msh3–/– and wild-type clones. The peaks occurred at either G or C in WGCW motifs (W = A or T), indicating that C was mutated on both DNA strands. This suggests that AID has limited entry points into V and S regions in vivo, and subsequent mutation requires Msh2-Msh6 and DNA polymerase.

Key Words: DNA repair enzymes • cytosine deamination • class switching • mutation hotspots • B lymphocytes

The online version of this article contains supplemental material.

Abbreviations used in this paper: AID, activation-induced cytidine deaminase; S, switch; V, variable.


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