title: Cutting edge: the G-U mismatch glycosylase methyl-CpG binding domain 4 is dispensable for somatic hypermutation and class switch recombination.
abstract: Affinity maturation of the humoral response is accomplished by somatic hypermutation and class switch recombination (CSR) of Ig genes. Activation-induced cytidine deaminase likely initiates these processes by deamination of cytidines in the V and switch regions of Ig genes. This activity is expected to produce G-U mismatches that can be substrates for MutS homolog 2/MutS homolog 6 heterodimers and for uracil DNA glycosylase. However, G-T and G-U mismatches are also substrates of the methyl-CpG binding domain 4 (Mbd4) glycosylase. To determine whether Mbd4 functions downstream of activation-induced cytidine deaminase activity, we examined somatic hypermutation and CSR in Mbd4(-/-) mice. In this study, we report that CSR, as analyzed by an in vitro switch assay and by in vivo immunizations, is unaffected in Mbd4(-/-) mice. In addition, the hypermutated JH2 to JH4 region in Peyer's patch B cells showed no effects as a result of Mbd4 deficiency. These data indicate that the Mbd4 glycosylase does not significantly contribute to mechanisms of Ab diversification.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Chanin 403, Bronx, NY 10461, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Bardwell
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
authors.forename: Edmund
authors.initials: E
authors.lastname: Wong
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Scharff
mesh_terms: D000818:Animals; D000916:Antibody Diversity / Q000235:genetics; D020137:Base Pair Mismatch / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D018899:CpG Islands / Q000276:immunology; D045647:DNA Glycosylases; D004260:DNA Repair / Q000276:immunology; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D006147:Guanine; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009699:N-Glycosyl Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin; D014498:Uracil
chemical_list: D007074:Immunoglobulin G; D014498:Uracil; D006147:Guanine; D004706:Endodeoxyribonucleases; D045647:DNA Glycosylases; C492249:Mbd4 protein, mouse; D009699:N-Glycosyl Hydrolases