title: A cis-acting diversification activator both necessary and sufficient for AID-mediated hypermutation.
abstract: Hypermutation of the immunoglobulin (Ig) genes requires Activation Induced cytidine Deaminase (AID) and transcription, but it remains unclear why other transcribed genes of B cells do not mutate. We describe a reporter transgene crippled by hypermutation when inserted into or near the Ig light chain (IgL) locus of the DT40 B cell line yet stably expressed when inserted into other chromosomal positions. Step-wise deletions of the IgL locus revealed that a sequence extending for 9.8 kilobases downstream of the IgL transcription start site confers the hypermutation activity. This sequence, named DIVAC for diversification activator, efficiently activates hypermutation when inserted at non-Ig loci. The results significantly extend previously reported findings on AID-mediated gene diversification. They show by both deletion and insertion analyses that cis-acting sequences predispose neighboring transcription units to hypermutation.
authors.affiliation: Institute for Molecular Radiobiology, Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Artem
authors.initials: A
authors.lastname: Blagodatski
authors.forename: Vera
authors.initials: V
authors.lastname: Batrak
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmidl
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schoetz
authors.forename: Randolph B
authors.initials: RB
authors.lastname: Caldwell
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arakawa
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Buerstedde
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D002645:Chickens; D002874:Chromosome Mapping; D003564:Cytidine Deaminase / Q000378:metabolism*; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D050439:Genes, Immunoglobulin Light Chain; D017930:Genes, Reporter; D014644:Genetic Variation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012045:Regulatory Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin; D014162:Transfection; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D049452:Green Fluorescent Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase