title: Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells.
abstract: Fanconi anemia is a rare genetic disorder that can lead to bone marrow failure, congenital abnormalities, and increased risk for leukemia and cancer. Cells with loss-of-function mutations in the FANC pathway are characterized by chromosome fragility, altered mutability, and abnormal regulation of the nonhomologous end-joining (NHEJ) pathway. Somatic hypermutation (SHM) and immunoglobulin (Ig) class switch recombination (CSR) enable B cells to produce high-affinity antibodies of various isotypes. Both processes are initiated after the generation of dG:dU mismatches by activation-induced cytidine deaminase. Whereas SHM involves an error-prone repair process that introduces novel point mutations into the Ig gene, the mismatches generated during CSR are processed to create double-stranded breaks (DSBs) in DNA, which are then repaired by the NHEJ pathway. As several lines of evidence suggest a possible role for the FANC pathway in SHM and CSR, we analyzed both processes in B cells derived from Fanca(-/-) mice. Here we show that Fanca is required for the induction of transition mutations at A/T residues during SHM and that despite globally normal CSR function in splenic B cells, Fanca is required during CSR to stabilize duplexes between pairs of short microhomology regions, thereby impeding short-range recombination downstream of DSB formation.
authors.affiliation: Centre National de la Recherche Scientifique UMR 8200, Institut Gustave Roussy, 94805 Villejuif, France Université Paris Sud, 91400 Orsay, France Programme Equipe Labellisées, Ligue Contre le Cancer, 75013 Paris, France.
authors.forename: Thuy Vy
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Université Paris Sud, 91400 Orsay, France Laboratoire de Radiopathologie, Service Cellules Souches et Radiation, Institut de Radiobiologie Cellulaire et Moléculaire, Direction des Sciences du Vivant, Commissariat à L'énergie Atomique et aux Énergies Alternatives, Institut National de la Santé et de la Recherche Médicale U967, 92265 Fontenay-aux-Roses, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Riou
authors.affiliation: Centre National de la Recherche Scientifique UMR 8200, Institut Gustave Roussy, 94805 Villejuif, France Université Paris Sud, 91400 Orsay, France filippo.rosselli@gustaveroussy.fr said.aoufouchi@gustaveroussy.fr.
authors.forename: Saïd
authors.initials: S
authors.lastname: Aoufouchi
authors.affiliation: Centre National de la Recherche Scientifique UMR 8200, Institut Gustave Roussy, 94805 Villejuif, France Université Paris Sud, 91400 Orsay, France Programme Equipe Labellisées, Ligue Contre le Cancer, 75013 Paris, France filippo.rosselli@gustaveroussy.fr said.aoufouchi@gustaveroussy.fr.
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D052217:Fanconi Anemia Complementation Group A Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052241:Fanconi Anemia Complementation Group G Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007134:Immunoglobulin Switch Region / Q000235:genetics; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*
chemical_list: C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052241:Fanconi Anemia Complementation Group G Protein; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein