title: The mismatch repair pathway functions normally at a non-AID target in germinal center B cells.
abstract: Deficiency in Msh2, a component of the mismatch repair (MMR) system, leads to an approximately 10-fold increase in the mutation frequency in most tissues. By contrast, Msh2 deficiency in germinal center (GC) B cells decreases the mutation frequency at the IgH V region as a dU:dG mismatch produced by AID initiates modifications by MMR, resulting in mutations at nearby A:T base pairs. This raises the possibility that GC B cells express a factor that converts MMR into a globally mutagenic pathway. To test this notion, we investigated whether MMR corrects mutations in GC B cells at a gene that is not mutated by AID. Strikingly, we found that GC B cells accumulate 5 times more mutations at a reporter gene than during the development of the mouse. Notably, the mutation frequency at this reporter gene was approximately 10 times greater in Msh2(-/-) compared with wild-type GC B cells cells. In contrast to the V region, the increased level of mutations at A:T base pairs in GC B cells was not caused by MMR. These results show that in GC B cells, (1) MMR functions normally at an AID-insensitive gene and (2) the frequency of background mutagenesis is greater in GC B cells than in their precursor follicular B cells.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Canada.
authors.forename: Blerta
authors.initials: B
authors.lastname: Green
authors.forename: Antoaneta
authors.initials: A
authors.lastname: Belcheva
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Nepal
authors.forename: Bryant
authors.initials: B
authors.lastname: Boulianne
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism* / Q000502:physiology; D053843:DNA Mismatch Repair / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D056968:Lac Repressors / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019076:Transgenes / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D056968:Lac Repressors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D051718:MutS Homolog 2 Protein