Activities Involved in V(D)J Recombination

Abstract

The assembly of Immunoglobulin (Ig) and T cell receptor (TCR) variable region gene segments (V, D, J) is a complex reaction that likely involves numerous components. In a simplified view, the recombination mechanism involves recognition of conserved heptamer-spacer-nonamer recombination sequences (RS) that flank each germline V, D, or J segment, Introduction of double stranded breaks between the elements to be joined and the flanking RS elements, potential loss and/or addition of nucleotides at the coding junctions, polymerization and ligation activities to complete the joining process (Fig.1; Alt and Baltimore 1982; for review see Blackwell and Alt 1989; Lieber 1991). The RS sequences that flank V, D, and J segments are sufficient to target the site-specific activities of the V(D)J recombination system to the adjacent “coding” sequences (Akira et al. 1987; Hesse et al. 1989). A notable aspect of this recombination reaction is the asymmetric processing of the coding and RS joins; the latter rarely involve nucleotide deletion and/or addition (Lieber 1991). The relative orientation of the sequences in the chromosome determines the fate of the reaction products. If the two coding gene sequences are in “opposite” transcriptional orientation the reaction will lead to inversion of the segment of DNA between the coding and RS joins with retention of all products in the chromosome. If the two sequences are in the same transcriptional orientation, the coding joins will be retained in the chromosome while the RS joins will be deleted as a circle (Okasaki and Sakano 1988; Toda et al. 1988; Fig.l). However, linear deletion products have also been observed to accumulate in thymus providing more direct evidence for the occurrence of double stranded breaks during this recombination process (Roth et al. 1992).