title: GANP regulates the choice of DNA repair pathway by DNA-PKcs interaction in AID-dependent IgV region diversification.
abstract: RNA export factor germinal center-associated nuclear protein (GANP) interacts with activation-induced cytidine deaminase (AID) and shepherds it from the cytoplasm to the nucleus and toward the IgV region loci in B cells. In this study, we demonstrate a role for GANP in the repair of AID-initiated DNA damage in chicken DT40 B cells to generate IgV region diversity by gene conversion and somatic hypermutation. GANP plays a positive role in IgV region diversification of DT40 B cells in a nonhomologous end joining-proficient state. DNA-PKcs physically interacts with GANP, and this interaction is dissociated by dsDNA breaks induced by a topoisomerase II inhibitor, etoposide, or AID overexpression. GANP affects the choice of DNA repair mechanism in B cells toward homologous recombination rather than nonhomologous end joining repair. Thus, GANP presumably plays a critical role in protection of the rearranged IgV loci by favoring homologous recombination of the DNA breaks under accelerated AID recruitment.
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Mohammed Mansour Abbas
authors.initials: MM
authors.lastname: Eid
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Sarah Ameen
authors.initials: SA
authors.lastname: Almofty
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan nobusaka@kumamoto-u.ac.jp.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D004260:DNA Repair / Q000235:genetics / Q000276:immunology*; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D056426:Genetic Loci / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004268:DNA-Binding Proteins; C481510:GANP protein, mouse; D007135:Immunoglobulin Variable Region; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase