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Chapter 29 : V(D)J Recombination

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Abstract:

This chapter focuses on V(D)J recombination, but other mechanisms also contribute to antigen receptor diversity. Although in mice and humans V(D)J recombination is the major source of diversity, this is not true of all vertebrates. Terminal deoxynucleotidyltransferase (TdT) is normally expressed only in early lymphoid cells, so these insertions are relatively specific to V(D)J recombination (compared with other types of double-strand break repair). Work of the past several years has shown that V(D)J recombination has two distinct stages. In the first stage, the RAG1 protein and RAG2 protein act together to recognize the RSSs and their correct 12/23 pairing, and make double-strand breaks at the border between each heptamer and the neighboring coding sequence. In the second stage, an array of factors also used in other types of ‘‘nonhomologous end joining’’ acts to assemble the coding joints and signal joints. The RAG1 and RAG2 proteins are the only lymphoid-specific factors needed for V(D)J recombination. RAG1 and RAG2 are normally coexpressed only in early lymphoid cells, where V(D)J recombination takes place. Transcription of the two neighboring RAG genes is convergent, and it has been shown that the control region of both genes is located upstream of RAG2. As for the regulation of V(D)J recombination, several new experimental systems should soon lead to a better understanding of locus accessibility, and make experimental modification of rearrangement possible.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29

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Figures

Image of Figure 1
Figure 1

. Recombination signal sequences and their arrangements at the antigen receptor loci. (A) The consensus sequence of an RSS, indicating the alternative spacer lengths of 12 or 23 bp. (B) The arrangements of RSSs at immunoglobulin and Tcell receptor loci. A 12-spacer RSS is indicated by an open triangle, a 23-spacer RSS by a filled triangle.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 2
Figure 2

Arrangements of RSSs and their products in recombination substrates. RSSs are denoted by triangles (open for a 12-RSS, filled for a 23-RSS), and their "coding" flanks are denoted by rectangles. Only the products that are retained in the substrate backbone after recombination are shown.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 3
Figure 3

The formation of self-complementary "P nucleotide" insertions in coding joints. During cleavage ofDNAat the RSS-coding border, the ends of coding DNA are converted to hairpins. These hairpins can be nicked a few bases off-center (shown here as one base off-center on the left end, two bases off-center on the right). This nicking leaves self-complementary single-strand extensions (large letters). After fill-in and joining, these extensions (marked P) can be incorporated in the junction.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 4
Figure 4

Nonstandard products of V(D)J recombination. Joining of one RSS to its partner's coding flank generates a hybrid joint. Breakage and rejoining of an RSS to its coding flank produces an open-and-shut joint, which can only be recognized if the junctional sequence has been altered. The local sequence changes in coding, hybrid, and open-and-shut joints are denoted by hatched boxes.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 5
Figure 5

DNA cleavage by the RAG proteins. In the first step, a nick is made at the 5′ end of the RSS heptamer, leaving a 3′-OH on the coding flank. In the second step, this hydroxyl group attacks the opposite strand to produce a hairpin coding end and a blunt signal end. In this figure, the reaction is shown as a coupled process at a pair of RSSs, as it would be in the presence of Mg (see text).

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 6
Figure 6

Hairpin formation by the RAG proteins at a singlestranded RSS. The 3′-OH on the duplex coding flank can attack the left or right end of the single-stranded RSS heptamer, producing either a normal coding end hairpin or a hairpin that also includes the RSS sequence.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 7
Figure 7

RAG-mediated reversal of cleavage. The hydroxyl group on an RSS end can attack the hairpin end of its partner RSS to make a hybrid joint (solid arrow), or can reattack its own hairpin end to make an open-and-shut joint (dashed arrow). Only the hybrid joint product is shown.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 8
Figure 8

One- or two-ended transposition by RAG1/2. The RAG proteins can insert an RSS end covalently into a target DNA. The reaction requires a 12/23 RSS pair, but may either insert a single RSS or insert both ends into opposite strands in a coupled reaction.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 9
Figure 9

RAG-mediated transposition and its reversal by disintegration. A cleaved signal end can attack a target DNA (double ellipse), and this reaction can also be reversed by the RAG proteins. The transposition can be single-ended, as is shown, or doubleended.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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Image of Figure 10
Figure 10

. A possible mode of chromosomal translocation by RAGpromoted transposition. A cleaved signal end at an Ig or TCR locus can insert into another chromosome (heavy lines) by transpositional strand transfer. In the resulting branchedDNAstructure, the 3′-OH of the targetDNAcan be processed further to generate a hairpin end and an interchromosomal junction containing the RSS. Because this reaction is likely to occur within a complex that also contains the hairpin coding end from the original cleavage, joining of the two hairpin ends would then generate the reciprocal chromosomal translocation.

Citation: Gellert M. 2002. V(D)J Recombination, p 705-729. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch29
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