| Summary: | 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 MutSalpha 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 MutSalpha heterodimers that maintain genomic stability. The similar defects on switching in Msh2(-/-), Msh2(-/-)Msh6(-/-) and Msh2(-/-)Msh6(-/-)Msh3(-/-) mice confirm that MutSalpha but not MutSbeta plays an important role in CSR. Analysis of SHM in Msh2(-/-)Msh6(-/-) mice not only confirmed the error-prone role of MutSalpha in the generation of strand biased mutations at A:T bases, but also revealed an error-free role of MutSalpha when repairing some of the dU:G mispairs generated by AID on both DNA strands. We propose a model for the role of MutSalpha 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.
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