Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule

Craig H. Bassing, Frederick W. Alt, Maureen M. Hughes, Margaux D'Auteuil, Tara D. Wehrly, Barbara B. Woodman, Frank Gärtner, J. Michael White, Laurie Davidson and Barry P. Sleckman ()
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Craig H. Bassing: Harvard Medical School and The Center for Blood Research
Frederick W. Alt: Harvard Medical School and The Center for Blood Research
Maureen M. Hughes: Washington University School of Medicine Department of Pathology and Immunology
Margaux D'Auteuil: Harvard Medical School and The Center for Blood Research
Tara D. Wehrly: Washington University School of Medicine Department of Pathology and Immunology
Barbara B. Woodman: Harvard Medical School and The Center for Blood Research
Frank Gärtner: Harvard Medical School and The Center for Blood Research
J. Michael White: Washington University School of Medicine Department of Pathology and Immunology
Laurie Davidson: Harvard Medical School and The Center for Blood Research
Barry P. Sleckman: Washington University School of Medicine Department of Pathology and Immunology

Nature, 2000, vol. 405, issue 6786, 583-586

Abstract: Abstract The genes encoding the variable regions of lymphocyte antigen receptors are assembled from variable (V), diversity (D) and joining (J) gene segments1. V(D)J recombination is initiated by the recombinase activating gene (RAG)-1 and -2 proteins, which introduce DNA double-strand breaks between the V, D and J segments and their flanking recombination signal sequences (RSSs). Generally expressed DNA repair proteins then carry out the joining reaction2,3. The conserved heptamer and nonamer sequences of the RSSs are separated by non-conserved spacers of 12 or 23 base pairs (forming 12-RSSs and 23-RSSs). The 12/23 rule, which is mediated at the level of RAG-1/2 recognition and cutting4,5, specifies that V(D)J recombination occurs only between a gene segment flanked by a 12-RSS and one flanked by a 23-RSS1. Vβ segments are appended to DJβ rearrangements, with little or no direct Vβ to Jβ joining, despite 12/23 compatibility of Vβ 23-RSSs and Jβ12-RSSs6,7. Here we use embryonic stem cells and mice with a modified T-cell receptor (TCR)β locus containing only one Dβ (Dβ1) gene segment and one Jβ (Jβ1) gene cluster to show that the 5′ Dβ1 12-RSS, but not the Jβ1 12-RSSs, targets rearrangement of a diverse Vβ repertoire. This targeting is precise and position-independent. This additional restriction on V(D)J recombination has important implications for the regulation of variable region gene assembly and repertoire development.

Date: 2000
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DOI: 10.1038/35014635

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