%0 Journal Article
%T MSH2/MSH6 Complex Promotes Error-Free Repair of AID-Induced dU:G Mispairs as well as Error-Prone Hypermutation of A:T Sites
%A Sergio Roa
%A Ziqiang Li
%A Jonathan U. Peled
%A Chunfang Zhao
%A Winfried Edelmann
%A Matthew D. Scharff
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0011182
%X 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 MutS¦Á 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 MutS¦Á heterodimers that maintain genomic stability. The similar defects on switching in Msh2£¿/£¿, Msh2£¿/£¿Msh6£¿/£¿ and Msh2£¿/£¿Msh6£¿/£¿Msh3£¿/£¿ mice confirm that MutS¦Á but not MutS¦Â plays an important role in CSR. Analysis of SHM in Msh2£¿/£¿Msh6£¿/£¿ mice not only confirmed the error-prone role of MutS¦Á in the generation of strand biased mutations at A:T bases, but also revealed an error-free role of MutS¦Á when repairing some of the dU:G mispairs generated by AID on both DNA strands. We propose a model for the role of MutS¦Á 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0011182