Indirect and direct evidence for DNA double–strand breaks in hypermutating immunoglobulin genes

Author:

Jacobs Heinz1,Rajewsky Klaus2,Fukita Yosho2,Bross Linda1

Affiliation:

1. Basel Institute for Immunology, Grenzacherstrasse 487, CH–4005 Basel, Switzerland

2. Institute for Genetics, University of Cologne, Weyertal 121, D–50931 Cologne, Germany

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, predefined 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 nonhomologous 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.

Publisher

The Royal Society

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

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