Hypothesis: A biological role for germline transcription in the mechanism of V(D)J recombination - implications for initiation of allelic exclusion

Abstract

The sequences that encode the antigen-binding sites of IgH and IgL chains - variable (V), diversity (D, H chain loci only) and joining (J) sequences - are configured as separate DNA segments at the germline level. Expression of an Ig molecule requires V(D)J assembly. Productive V(D)J recombination is monoallelic. How rearrangement is initiated differentially at maternal and paternal alleles is unclear. The products of recombination activating gene (RAG)1 and RAG2 mediate rearrangement by cleaving the DNA between an unrearranged gene segment and adjacent recombination signal sequences (RSS). It is proposed that supercoiling generated during germline transcription at Ig loci (which occurs concomitantly with rearrangement) is required at RSS for RAG1/2 recognition. Rearrangement might hence initiate sequentially at maternal and paternal alleles where deregulated germline transcription causes RAG1/2 recognition of RSS to become stochastic. Show more