title: Alternative splicing regulates activation-induced cytidine deaminase (AID): implications for suppression of AID mutagenic activity in normal and malignant B cells.
abstract: The mutagenic enzyme activation-induced cytidine deaminase (AID) is required for immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) in germinal center (GC) B cells. Deregulated expression of AID is associated with various B-cell malignancies and, currently, it remains unclear how AID activity is extinguished to avoid illegitimate mutations. AID has also been shown to be alternatively spliced in malignant B cells, and there is limited evidence that this also occurs in normal blood B cells. The functional significance of these splice variants remains unknown. Here we show that normal GC human B cells and blood memory B cells similarly express AID splice variants and show for the first time that AID splicing variants are singly expressed in individual normal B cells as well as malignant B cells from chronic lymphocytic leukemia patients. We further demonstrate that the alternative AID splice variants display different activities ranging from inactivation of CSR to inactivation or heightened SHM activity. Our data therefore suggest that CSR and SHM are differentially switched off by varying the expression of splicing products of AID at the individual cell level. Most importantly, our findings suggest a novel tumor suppression mechanism by which unnecessary AID mutagenic activities are promptly contained for GC B cells.
authors.affiliation: Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Wu
authors.forename: Jaime R
authors.initials: JR
authors.lastname: Darce
authors.forename: Sook Kyung
authors.initials: SK
authors.lastname: Chang
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D017124:Conserved Sequence; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase