title: Binding of AID to DNA does not correlate with mutator activity.
abstract: The DNA deaminase activation-induced cytidine deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) by deaminating cytidines to uridines at V region (V) genes and switch (S) regions. The mechanism by which AID is recruited to V genes and S region DNA is poorly understood. In this study, we used the CH12 B lymphoma line to demonstrate that, although S regions can efficiently recruit AID and undergo mutations and deletions, AID neither binds to nor mutates the V gene, thus clearly demonstrating intraimmunoglobulin locus specificity. Depletion of the RNA-binding protein polypyrimidine tract binding protein-2, previously shown to promote recruitment of AID to S regions, enables stable association of AID with the V gene. Surprisingly, AID binding to the V gene does not induce SHM. These results unmask a striking lack of correlation between AID binding and its mutator activity, providing evidence for the presence of factors required downstream of AID binding to effect SHM. Furthermore, our findings suggest that S regions are preferred targets for AID and, aided by polypyrimidine tract binding protein-2, act as "sinks" to sequester AID activity from other genomic regions.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, NY 10065; andImmunology and Microbial Pathogenesis Program, Weill-Cornell Medical School, New York, NY 10065.
authors.forename: Allysia J
authors.initials: AJ
authors.lastname: Matthews
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, NY 10065; andImmunology and Microbial Pathogenesis Program, Weill-Cornell Medical School, New York, NY 10065.
authors.forename: Solomon
authors.initials: S
authors.lastname: Husain
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, NY 10065; andImmunology and Microbial Pathogenesis Program, Weill-Cornell Medical School, New York, NY 10065 chaudhuj@mskcc.org.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D004247:DNA / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D017384:Sequence Deletion / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D009419:Nerve Tissue Proteins; C429773:Ptbp2 protein, mouse; D038941:Polypyrimidine Tract-Binding Protein; D004247:DNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase