The Mechanism and Regulation of Chromosomal V(D)J Recombination

Abstract

V(D)J recombination is of fundamental importance to the generation of diverse antigen receptor repertoires. We review our current understanding of the V(D)J recombination reaction and how it is regulated during lymphocyte development. We also discuss how defects in the mechanism or regulation of V(D)J recombination can lead to human disease.

TEA regulates local TCR‐Jα accessibility through histone acetylation

“…In an attempt to characterize the molecular events that direct the accessibility, a very important study has shown that the RAG complex can access chromosomal RSS only in lymphoid cells and only in the lineage-specific loci (e.g: the Ig loci only in the pro-B cells; the TCR loci only in the pro-T cells) [6]. As this seemed to point to specific chromatin properties, subsequent studies have focused on the role of the nucleosomal structure [7,8]. All the in vitro results obtained so far seem to confirm that a nucleosomal RSS is refractory to binding and cleavage by the RAG proteins [9][10][11]; the studies, however, diverge with regards to the possibility to overcome the block by acetylating the tails of the histones.…”

The Eλ3–1 enhancer is essential for V(D)J recombination of the murine immunoglobulin lambda light chain locus

“…To distinguish this BAC from the endogenous Ig locus, a cMyc tag (39 bp) was introduced into the C 1 constant region so that it inserted into, and destroyed, the Xho I site; this generated the BAC, C 1 -T ( Figure 1B). …”

“…The generation of an accessible chromatin structure at the RSSs is central to this regulation (reviewed by [1]) and knock-out studies have shown that tissuespecific enhancers play an essential role in regulating this accessibility by restricting it to the correct cell and the correct stage of lymphocyte development [2]. Recombination enhancers have been identified for most immunoglobulin and T cell receptor loci and are often identical to the enhancers that upregulate transcription of the rearranged gene [3].…”

“…It spans only 240 kb on chromosome 16 and contains two gene clusters that appear to have arisen by duplication (reviewed by [5]). Each cluster contains 1-2 variable gene segments followed by two joining/constant (J/C) regions, in the order V 2 -V x -JC 2 -JC 4 --V 1 -JC 3 -JC 1 [6,7]; since JC 4 is a pseudogene, the locus undergoes only four main rearrangements: V 1 -J 1 , V 2 -J 2 V x -J 2 and V 1 -J 3 that occur in the ratio 3:2:2:1 [8,9]. However, V 2 can also recombine with JC 1 or JC 3 , albeit infrequently [10].…”

“…Therefore, the regulatory elements were analysed using a BAC construct that encodes the 3' half of the Iglocus from the hypersensitive site 5' of V 1 (hsV 1 ) to the four hypersensitive sites that lie downstream of JC 3 (HS1-4; Figure 1B). Transgenic mice were generated and recombination examined in mice carrying the wild type BAC and those carrying deletions of each of the downstream hypersensitive sites.…”