title: Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase.
abstract: Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated in activated B lymphocytes by activation-induced deaminase (AID). AID is thought to make lesions in DNA by deaminating cytidine residues in single-stranded DNA exposed by RNA polymerase during transcription. Although this must occur in the nucleus, AID is found primarily in the cytoplasm. Here we show that AID is actively excluded from the nucleus by an exportin CRM1-dependent pathway. The AID nuclear export signal (NES) is found at the carboxyl terminus of AID in a region that overlaps a sequence required for CSR but not SHM. We find that AID lacking a functional NES causes more hypermutation of a nonphysiologic target gene in transfected fibroblasts. However, the NES does not impact on the rate of mutation of immunoglobulin genes in B lymphocytes, suggesting that the AID NES does not limit AID activity in these cells.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: McBride
authors.forename: Vasco
authors.initials: V
authors.lastname: Barreto
authors.forename: Almudena R
authors.initials: AR
authors.lastname: Ramiro
authors.forename: Pete
authors.initials: P
authors.lastname: Stavropoulos
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000595:Amino Acid Sequence; D000619:Aminohydrolases / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D028884:Karyopherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D016133:Polymerase Chain Reaction; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics* / Q000276:immunology*; D000097606:Exportin 1 Protein
chemical_list: D000619:Aminohydrolases; D017931:DNA Primers; D028884:Karyopherins; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D000097606:Exportin 1 Protein