title: Combined deficiency of MSH2 and Sμ region abolishes class switch recombination.
abstract: Class switch recombination (CSR) is mediated by G-rich tandem repeated sequences termed switch regions. Transcription of switch regions generates single-stranded R loops that provide substrates for activation-induced cytidine deaminase. Mice deficient in MSH2 have a mild defect in CSR and analysis of their switch junctions has led to a model in which MSH2 is more critical for switch recombination events outside than within the tandem repeats. It is also known that deletion of the whole Sμ region severely impairs but does not abrogate CSR despite the lack of detectable R loops. Here, we demonstrate that deficiency of both MSH2 and the Sμ region completely abolishes CSR and that the abrogation occurs at the genomic level. This finding further supports the crucial role of MSH2 outside the tandem repeats. It also indicates that during CSR, MSH2 has access to activation-induced cytidine deaminase targets in R-loop-deficient Iμ-Cμ sequences rarely used in CSR, suggesting an MSH2-dependent DNA processing activity at the Iμ exon that may decrease with transcription elongation across the Sμ region.
authors.affiliation: CNRS UMR5089, Institut de Pharmacologie et de Biologie Structurale, Equipe Instabilité génétique et régulation transcriptionnelle, Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Leduc
authors.forename: Dania
authors.initials: D
authors.lastname: Haddad
authors.forename: Nathalie
authors.initials: N
authors.lastname: Laviolette-Malirat
authors.forename: Ngoc-Sa
authors.initials: NS
authors.lastname: Nguyen Huu
authors.forename: Ahmed Amine
authors.initials: AA
authors.lastname: Khamlichi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007134:Immunoglobulin Switch Region / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D051718:MutS Homolog 2 Protein