ArticlePhilosophical transactions of the Royal Society of London. Series B, Biological sciences2001
Indirect and direct evidence for DNA double-strand breaks in hypermutating immunoglobulin genes.
Article in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
5 citing papers in PubMed.
- A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair.The Journal of experimental medicine · 2007Article
- Codon insertion and deletion functions as a somatic diversification mechanism in human antibody repertoires.Biology direct · 2006Article
- The configuration of the immunoglobulin genes in B cell chronic lymphocytic leukemia.Leukemia · 2002Review
- AID-GFP chimeric protein increases hypermutation of Ig genes with no evidence of nuclear localization.Proceedings of the National Academy of Sciences of the United States of America · 2002Article
- Generation of aberrant transcripts of and free DNA ends in zebrafish no tail gene.Marine biotechnology (New York, N.Y.)Article
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Authors and funding
4 authors.
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No grant is acknowledged in the PubMed record.
Abstract
The generation of a diverse antigen receptor repertoire is fundamental for the functionality of the adaptive immune system. While the V(D)J recombination process that generates the primary antigen receptor repertoire is understood in great detail, it is still unclear by which mechanism immunoglobulin (Ig) genes are further diversified by somatic hypermutation. Using mouse strains that carry a non-functional, pre-defined V(H)D(H)J(H) gene segment in their IgH locus we demonstrate DNA double-strand breaks (DSBs) in and around V(H)D(H)J(H) in B cells undergoing somatic hypermutation. The generation of these DSBs depends on transcriptional activity, and their distribution along the V(H)D(H)J(H) segment parallels that of point mutations in the hypermutation domain. Furthermore, similar to hot spots of somatic hypermutation, 50-60% of all DSBs occur preferentially at RGYW motifs. DSBs may transiently dissociate the Ig promoter from the intronic enhancer to block further transcription and to initiate an error-prone non-homologous DSB repair pathway. In accord with this model large deletions are frequently produced, along with point mutations, in a V(H)D(H)J(H) segment inserted together with its promoter into the IgH locus in inverted orientation. Our data suggest that DSBs are reaction intermediates of the mechanism underlying somatic hypermutation.
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