title: Alternative end joining during switch recombination in patients with ataxia-telangiectasia.
abstract: Ataxia-Telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic diseases with similar cellular phenotypes that are caused by mutations in the recently described ATM (encoding ATM) and NBS1 (encoding p95) genes, respectively. Both disorders are accompanied by immunodeficiency in a majority of patients, but the mechanism involved has as yet not been established. We demonstrate that in cells from A-T patients, the switch (S) recombination junctions are aberrant and characterized by a strong dependence on short sequence homologies and devoid of normally occurring mutations around the breakpoint. A low number of S fragments were generated in cells from NBS patients and showed only limited dependence on sequence identity and mutation frequencies were similar to those observed in normal controls. We propose that ATM and p95 are both involved in the final step(s) in class switch recombination with related, but disparate, functional roles. Thus, the general pathway involved in DNA repair also has a major influence on the immunoglobulin isotype switching process.
authors: Division of Clinical Immunology, IMPI, Karolinska Institutet at Huddinge Hospital, and Center for Biotechnology and Center for Oral Biology, NOVUM, Huddinge, Sweden.
authors: Qiang
authors: Q
authors: Pan
authors: Corinne
authors: C
authors: Petit-Frére
authors: Aleksi
authors: A
authors: Lähdesmäki
authors: Hanna
authors: H
authors: Gregorek
authors: Krystyna H
authors: KH
authors: Chrzanowska
authors: Lennart
authors: L
authors: Hammarström
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000276:immunology*; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics / Q000276:immunology; D007070:Immunoglobulin A / Q000097:blood / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011995:Recombination, Genetic; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases