Abstract
Mismatch repair of AID-generated dU:G mispairs is critical for class switch recombination (CSR) and somatic hypermutation (SHM) in B cells. The generation of a previously unavailable Msh2−/−Msh6−/− mouse has for the first time allowed us to examine the impact of the complete loss of MutSα on lymphomagenesis, CSR and SHM. The onset of T cell lymphomas and the survival of Msh2−/−Msh6−/− and Msh2−/−Msh6−/−Msh3−/− mice are indistinguishable from Msh2−/− mice, suggesting that MSH2 plays the critical role in protecting T cells from malignant transformation, presumably because it is essential for the formation of stable MutSα heterodimers that maintain genomic stability. The similar defects on switching in Msh2−/−, Msh2−/−Msh6−/− and Msh2−/−Msh6−/−Msh3−/− mice confirm that MutSα but not MutSβ plays an important role in CSR. Analysis of SHM in Msh2−/−Msh6−/− mice not only confirmed the error-prone role of MutSα in the generation of strand biased mutations at A:T bases, but also revealed an error-free role of MutSα when repairing some of the dU:G mispairs generated by AID on both DNA strands. We propose a model for the role of MutSα at the immunoglobulin locus where the local balance of error-free and error-prone repair has an impact in the spectrum of mutations introduced during Phase 2 of SHM.
Highlights
Immunoglobulin (Ig) genes undergo somatic hypermutation (SHM) to produce high affinity antigen binding sites and class switch recombination (CSR). These processes allow the antibodies to bind antigens strongly and to carry out different effector functions and be distributed throughout the body so that they can inactivate pathogens and other toxic substances. Both SHM and CSR are initiated by activation-induced cytidine deaminase (AID), which is highly expressed in germinal center B cells [1] and is primarily targeted to antibody variable (V) and switch (S) regions
We first bred Msh2+/2 mice with Msh6+/2 mice that had been fully backcrossed to the C57BL/6 strain to generate Msh2+/2Msh6+/2 mice in which Msh2 mutant allele and Msh6 mutant allele were in a trans position
After screening more than 300 pups, one such Msh22/2Msh6+/2 mouse was identified. This Msh22/2Msh6+/2 mouse was bred with a wild type C57BL/6 mouse to generate Msh2+/2Msh6+/2 mice in which the defective Msh22 and Msh62 genes were in cis (Figure 1)
Summary
Immunoglobulin (Ig) genes undergo somatic hypermutation (SHM) to produce high affinity antigen binding sites and class switch recombination (CSR). To further explore the roles of MSH2 and MSH6 in tumorigenesis, in CSR and in SHM at A:T bases, it would be useful to analyze mice simultaneously lacking both proteins and completely deficient in MutSa complex dependent functions [7].
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