ATM is required for efficient recombination between immunoglobulin switch regions.
Ataxia telangiectasia mutated (ATM) kinase is critical for initiating the signaling pathways that lead to cell cycle checkpoints and DNA double strand break repair. In the absence of ATM, humans and mice show a primary immunodeficiency that includes low serum antibody titers, but the role of ATM in antigen-driven immunoglobulin gene diversification has not been defined. Here, we show that although ATM is dispensable for somatic hypermutation, it is required for efficient class switch recombination (CSR). The defect in CSR is not due to alterations in switch region transcription, accessibility, DNA damage checkpoint protein recruitment, or short-range intra-switch region recombination. Only long-range inter-switch recombination is defective, indicating an unexpected role for ATM in switch region synapsis during CSR.
Reina-San-Martin
Bernardo
B
Howard Hughes Medical Institute, The Rockefeller University, 1230 York Ave., New York, NY 10021, USA.
Chen
Hua Tang
HT
Nussenzweig
André
A
Nussenzweig
Michel C
MC
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000276:immunology*; D015139:Blotting, Southern; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008815:Mice, Inbred Strains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000276:immunology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases