title: Target DNA sequence directly regulates the frequency of activation-induced deaminase-dependent mutations.
abstract: Activation-induced deaminase (AID) catalyses class switch recombination (CSR) and somatic hypermutation (SHM) in B lymphocytes to enhance Ab diversity. CSR involves breaking and rejoining highly repetitive switch (S) regions in the IgH (Igh) locus. S regions appear to be preferential targets of AID. To determine whether S region sequence per se, independent of Igh cis regulatory elements, can influence AID targeting efficiency and mutation frequency, we established a knock-in mouse model by inserting a core Sγ1 region into the first intron of proto-oncogene Bcl6, which is a non-Ig target of SHM. We found that the mutation frequency of the inserted Sγ1 region was dramatically higher than that of the adjacent Bcl6 endogenous sequence. Mechanistically, S region-enhanced SHM was associated with increased recruitment of AID and RNA polymerase II, together with Spt5, albeit to a lesser extent. Our studies demonstrate that target DNA sequences influence mutation frequency via regulating AID recruitment. We propose that the nucleotide sequence preference may serve as an additional layer of AID regulation by restricting its mutagenic activity to specific sequences despite the observation that AID has the potential to access the genome widely.
authors.affiliation: Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Health, Denver, CO 80206, USA.
authors.forename: Zhangguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Sawanee S
authors.initials: SS
authors.lastname: Viboolsittiseri
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Connor
authors.forename: Jing H
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000818:Animals; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D055879:Gene Knock-In Techniques / Q000379:methods; D006801:Humans; D007134:Immunoglobulin Switch Region / Q000235:genetics; D051379:Mice; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D012319:RNA Polymerase II / Q000235:genetics; D011995:Recombination, Genetic / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D012319:RNA Polymerase II; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase