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

Academic Article

Abstract

  • The genes encoding the variable regions of lymphocyte antigen receptors are assembled from variable (V), diversity (D) and joining (J) gene segments. 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 reaction. 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 cutting, specifies that V(D)J recombination occurs only between a gene segment flanked by a 12-RSS and one flanked by a 23-RSS. 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-RSSs. 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.
  • Authors

    Published In

  • Nature  Journal
  • Digital Object Identifier (doi)

    Author List

  • Bassing CH; Alt FW; Hughes MM; D'Auteuil M; Wehrly TD; Woodman BB; Gärtner F; White JM; Davidson L; Sleckman BP
  • Start Page

  • 583
  • End Page

  • 586
  • Volume

  • 405
  • Issue

  • 6786