MSH2/MSH6 complex promotes error-free repair of AID-induced dU:G mispairs as well as error-prone hypermutation of A:T sites.
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.
Roa
Sergio
S
Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, USA.
Li
Ziqiang
Z
Peled
Jonathan U
JU
Zhao
Chunfang
C
Edelmann
Winfried
W
Scharff
Matthew D
MD
D000818:Animals; D020137:Base Pair Mismatch; D003564:Cytidine Deaminase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D019281:Dimerization; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D011995:Recombination, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein