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A Role for the MutL Mismatch Repair Mlh3 Protein in Immunoglobulin Class Switch DNA Recombination and Somatic Hypermutation¹

Xiaoping Wu^*, Connie Y. Tsai^*, Marienida B. Patam^*, Hong Zan^*, Jessica P. Chen, Steve M. Lipkin and Paolo Casali^2,*,

^* Center for Immunology and Department of Medicine, School of Medicine and School of Biological Sciences, University of California, Irvine, CA 92697

Class switch DNA recombination (CSR) and somatic hypermutation (SHM) are central to the maturation of the Ab response. Both processes involve DNA mismatch repair (MMR). MMR proteins are recruited to dU:dG mispairs generated by activation-induced cytidine deaminase-mediated deamination of dC residues, thereby promoting S-S region synapses and introduction of mismatches (mutations). The MutL homolog Mlh3 is the last complement of the mammalian set of MMR proteins. It is highly conserved in evolution and is essential to meiosis and microsatellite stability. We used the recently generated knockout mlh3^–/– mice to address the role of Mlh3 in CSR and SHM. We found that Mlh3 deficiency alters both CSR and SHM. mlh3^–/– B cells switched in vitro to IgG and IgA but displayed preferential targeting of the RGYW/WRCY (R = A or G, Y = C or T, W = A or T) motif by S1 and S3 breakpoints and introduced more insertions and fewer donor/acceptor microhomologies in Sµ-S1 and Sµ-S3 DNA junctions, as compared with mlh3^+/+ B cells. mlh3^–/– mice showed only a slight decrease in the frequency of mutations in the intronic DNA downstream of the rearranged J_H4 gene. However, the residual mutations were altered in spectrum. They comprised a decreased proportion of mutations at dA/dT and showed preferential RGYW/WRCY targeting by mutations at dC/dG. Thus, the MMR Mlh3 protein plays a role in both CSR and SHM.

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The JI 2006 176: 5131-5132. [Full Text]  

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