The MRE11-RAD50-NBS1 complex accelerates somatic hypermutation and gene conversion of immunoglobulin variable regions

Targeted diversification of immunoglobulin variable regions is induced by activation-induced deaminase and may occur by either somatic hypermutation or gene conversion. MRE11-RAD50-NBS1 (MRN) is a ubiquitous and conserved nuclease complex critical for DNA break repair and is essential in class-switc...

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Bibliographic Details
Published in:Nature Immunology 2005-07, Vol.6 (7), p.730-736
Main Authors: Maizels, Nancy, Yabuki, Munehisa, Fujii, Monica M
Format: Article
Language:English
Subjects:
Acid Anhydride Hydrolases
Animals
B-Lymphocytes - immunology
Base Sequence
Biomedical and Life Sciences
Biomedicine
Cell Cycle Proteins - genetics
Cell Cycle Proteins - immunology
Cell Line, Tumor
Chickens
Deoxyribonucleic acid
DNA
DNA Repair Enzymes - genetics
DNA Repair Enzymes - immunology
DNA, Neoplasm - chemistry
DNA, Neoplasm - genetics
DNA-Binding Proteins - genetics
DNA-Binding Proteins - immunology
Gene Conversion - genetics
Gene Conversion - immunology
Humans
Immunoglobulin Variable Region - genetics
Immunoglobulin Variable Region - immunology
Immunology
Infectious Diseases
Lesions
Molecular Sequence Data
MRE11 Homologue Protein
Multiprotein Complexes - genetics
Multiprotein Complexes - immunology
Nuclear Proteins - genetics
Nuclear Proteins - immunology
Nucleoside Deaminases - immunology
Polymerase Chain Reaction
Recombination, Genetic
Sequence Alignment
Sequence Analysis, DNA
Somatic Hypermutation, Immunoglobulin - genetics
Somatic Hypermutation, Immunoglobulin - immunology
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Summary:Targeted diversification of immunoglobulin variable regions is induced by activation-induced deaminase and may occur by either somatic hypermutation or gene conversion. MRE11-RAD50-NBS1 (MRN) is a ubiquitous and conserved nuclease complex critical for DNA break repair and is essential in class-switch recombination. Here we show that ectopic expression of NBS1, the regulatory subunit of MRN, accelerated hypermutation in the human B cell line Ramos and accelerated gene conversion in the chicken B cell line DT40. In both cases, accelerated diversification depended on MRN complex formation. These data suggest that MRN promotes DNA cleavage and/or mutagenic repair of lesions initiated by activation-induced deaminase, acting in the shared pathway of immunoglobulin gene diversification.
ISSN:1529-2908
1529-2916
1365-2567
DOI:10.1038/ni1215