title: MBD4 Facilitates Immunoglobulin Class Switch Recombination.
abstract: Immunoglobulin heavy chain class switch recombination (CSR) requires targeted formation of DNA double-strand breaks (DSBs) in repetitive switch region elements followed by ligation between distal breaks. The introduction of DSBs is initiated by activation-induced cytidine deaminase (AID) and requires base excision repair (BER) and mismatch repair (MMR). The BER enzyme methyl-CpG binding domain protein 4 (MBD4) has been linked to the MMR pathway through its interaction with MutL homologue 1 (MLH1). We find that when Mbd4 exons 6 to 8 are deleted in a switching B cell line, DSB formation is severely reduced and CSR frequency is impaired. Impaired CSR can be rescued by ectopic expression of Mbd4 Mbd4 deficiency yields a deficit in DNA end processing similar to that found in MutS homologue 2 (Msh2)- and Mlh1-deficient B cells. We demonstrate that microhomology-rich S-S junctions are enriched in cells in which Mbd4 is deleted. Our studies suggest that Mbd4 is a component of MMR-directed DNA end processing.
authors: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Fernando
authors: F
authors: Grigera
authors: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Robert
authors: R
authors: Wuerffel
authors: Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA star1@uic.edu.
authors: Amy L
authors: AL
authors: Kenter
mesh_terms: D000818:Animals; D001483:Base Sequence; D064113:CRISPR-Cas Systems / Q000235:genetics; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D005816:Genetic Complementation Test; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D004706:Endodeoxyribonucleases; C492249:Mbd4 protein, mouse
keywords: B cells; Ig class switch; Ig class switch recombination; mismatch repair; uracil glycosylase