title: Cyclin-dependent kinases regulate Ig class switching by controlling access of AID to the switch region.
abstract: Ig class switching requires cell proliferation and is division linked, but the detailed mechanism is unknown. By analyzing the first switching cells early in the kinetics, our analysis suggested that proliferating B cells had a very short G1 phase (<3.5 h), a total cell cycle time of ∼ 11 h, and that Ig class switching preferentially occurred in the late G1 or early S phase. Inhibition of cyclin-dependent kinases (CDKs) caused dramatic reduction of switching rate within 6 h. This was associated with less targeting of activation-induced cytidine deaminase (AID) to the Igh locus. Interestingly, ectopically expressed nuclear AID in HeLa cells was preferentially found in the early S phase. Furthermore, in CDK2 hypomorphic cells there was reduced nuclear AID accumulation. Thus, our data are compatible with the idea that division-linked Ig class switching is in part due to CDK2-regulated AID nuclear access at the G1/S border.
authors: Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden;
authors: Minghui
authors: M
authors: He
authors: Division of Gerontology and Geriatric Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136;
authors: Elena M
authors: EM
authors: Cortizas
authors: Division of Gerontology and Geriatric Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136; and Geriatric Research, Education, and Clinical Center, Miami Veterans Affairs Healthcare System, Miami, FL 33125.
authors: Ramiro E
authors: RE
authors: Verdun
authors: Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden; eva.severinson@su.se.
authors: Eva
authors: E
authors: Severinson
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000378:metabolism*; D004261:DNA Replication; D006801:Humans; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000235:genetics; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase