title: Complex relationship between mismatch repair proteins and MBD4 during immunoglobulin class switch recombination.
abstract: Mismatch repair (MMR) safeguards against genomic instability and is required for efficient Ig class switch recombination (CSR). Methyl CpG binding domain protein 4 (MBD4) binds to MutL homologue 1 (MLH1) and controls the post-transcriptional level of several MMR proteins, including MutS homologue 2 (MSH2). We show that in WT B cells activated for CSR, MBD4 is induced and interacts with MMR proteins, thereby implying a role for MBD4 in CSR. However, CSR is in the normal range in Mbd4 deficient mice deleted for exons 2-5 despite concomitant reduction of MSH2. We show by comparison in Msh2(+/-) B cells that a two-fold reduction of MSH2 and MBD4 proteins is correlated with impaired CSR. It is therefore surprising that CSR occurs at normal frequencies in the Mbd4 deficient B cells where MSH2 is reduced. We find that a variant Mbd4 transcript spanning exons 1,6-8 is expressed in Mbd4 deficient B cells. This transcript can be ectopically expressed and produces a truncated MBD4 peptide. Thus, the 3' end of the Mbd4 locus is not silent in Mbd4 deficient B cells and may contribute to CSR. Our findings highlight a complex relationship between MBD4 and MMR proteins in B cells and a potential reconsideration of their role in CSR.
authors.affiliation: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, United States of America.
authors.forename: Fernando
authors.initials: F
authors.lastname: Grigera
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bellacosa
authors.forename: Amy L
authors.initials: AL
authors.lastname: Kenter
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D053843:DNA Mismatch Repair / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000235:genetics*; D005091:Exons / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics*; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D009687:Nuclear Proteins; D004706:Endodeoxyribonucleases; C492249:Mbd4 protein, mouse; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein