Interallelic V(D)J trans-rearrangement within the beta T cell receptor gene is infrequent and occurs preferentially during attempted D beta to J beta joining.

Aster, Jon C.; Sklar, Jeffrey

doi:10.1084/jem.175.6.1773

Cited by 13 publications

(7 citation statements)

References 38 publications

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“…4). Seven positions previously highlighted as important to function, in vivo, for the canonical joining signal (CACA [1][2][3][4] of the heptamer and A 5 , A 6 , and A 7 of the nonamer [1,34]) appear together in only two cryptic signals in the plasmid collection (Fig. 4A, IMP).…”

Section: V(d)j Recombination Is An Obligatory Part Of T-and B-cell Dementioning

confidence: 99%

Cryptic Signals and the Fidelity of V(D)J Joining

Lewis

Agard

Suh

et al. 1997

Molecular and Cellular Biology

131

120

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V(D)J recombination is responsible for the de novo creation of antigen receptor genes in T-and B-cell precursors. To the extent that lymphopoiesis takes place throughout an animal's lifetime, recombination errors present an ongoing problem. One type of aberrant rearrangement ensues when DNA sequences resembling a V(D)J joining signal are targeted by mistake. This study investigates the type of sequence likely to be subject to mistargeting, the level of joining-signal function associated with these sequences, and the number of such cryptic joining signals in the genome.In a vertebrate, many millions of B and T cells are produced daily. A pivotal event in B-and T-cell differentiation is the assembly, through DNA recombination, of antigen receptor genes (reviewed in reference 43). Recombination is mediated by two key proteins, called RAG1 and RAG2, as well as an incompletely defined collection of other enzymes and factors (reviewed in references 28 and 56). During pre-B-cell and pre-T-cell development, DNA segments termed V, D, and J are assembled to form the variable exon of the expressed immunoglobulin (Ig) and T-cell receptor (TCR) genes. The joined gene segments encode the highly variable antigen-binding domain of the antigen receptor protein.V(D)J assembly is accomplished through DNA rearrangements that can encompass up to several megabases. The sequence motifs that serve as recognition elements for this process (joining signals) are surprisingly compact. A joining signal, found adjacent to every V, D, or J segment, is comprised of a heptamer (CACAGTG), a spacer (of 12 or 23 bp), and a nonamer (ACAAAAACC) (Fig. 1A). No sequence apart from the 28 (or 39)-bp joining signal motif is required for sitespecific recognition and recombination (reference 33 and references cited therein).Any V(D)J recombination event is normally an interaction between two gene segments, one of which possesses a 12-bp spacer (12-spacer) signal, and the other of which possesses a 23-bp spacer (23-spacer) signal. The molecular signature of V(D)J recombination is production of two types of junctions. One of these, the coding joint, is formed from the fusion of the two coding sequences (e.g., V and J), and the other, a signal joint, is formed from the corresponding joining signals. It is usual for a coding joint to have a small and variable degree of base loss and insertion at the point where the two coding elements connect, whereas the signal joint is typified by a precise fusion, heptamer to heptamer, of the two signals.Not surprisingly, DNA sequences that resemble an authentic joining signal (cryptic signals) are sometimes rearranged by mistake (first described in reference 36). The result is the production of recombinant junctions that are structurally analogous to coding joints and signal joints (Fig. 1) (17, 36). In this report, we take production of the characteristic junctions as the defining, diagnostic feature of a cryptic signal.Cryptic signals are seen at several of the Ig and TCR loci in both mice and humans and are active in re...

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Section: V(d)j Recombination Is An Obligatory Part Of T-and B-cell Dementioning

confidence: 99%

Cryptic Signals and the Fidelity of V(D)J Joining

Lewis

Agard

Suh

et al. 1997

Molecular and Cellular Biology

131

120

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“…We infer that these mechanisms do not function, or function inefficiently, with transiently transfected extrachromosomal elements. Although the nature of these mechanisms are unknown, it is reasonable to think that they act to inhibit synapsis of inappropriate RSS pairs, either those on different chromosomes or in different antigen receptor loci (38).…”

Section: Cis Versus Trans and The Effect Of Substrate Topological Stamentioning

confidence: 99%

Intermolecular V(D)J Recombination

Tevelev¹,

Schatz

2000

Journal of Biological Chemistry

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V(D)J recombination plays a prominent role in the generation of the antigen receptor repertoires of B and T lymphocytes. It is also likely to be involved in the formation of chromosomal translocations, some of which may result from interchromosomal recombination. We have investigated the potential of the V(D)J recombination machinery to perform intermolecular recombination between two plasmids, either unlinked or linked by catenation. In either case, recombination occurs in trans to yield signal and coding joints, and the results do not support the existence of a mechanistic block to the formation of coding joints in trans. Instead, we observe that linearization of the substrate, which does not alter the cis or trans status of the recombination signals, causes a specific and dramatic reduction in coding joint formation. This unexpected result leads us to propose a "release and recapture" model for V(D)J recombination in which coding ends are frequently released from the postcleavage complex and the efficiency of coding joint formation is influenced by the efficiency with which such ends are recaptured by the complex. This implies the existence of mechanisms, operative during recombination of chromosomal substrates, that act to prevent coding end release or to facilitate coding end recapture.V(D)J recombination is the process of assembly of T-cell receptor and immunoglobulin genes from V, J, and sometimes D gene segments (1). Lymphoid-specific proteins RAG1 (recombination activating gene 1) and RAG2 (2, 3) and multiple ubiquitously expressed protein factors are essential for V(D)J recombination. RAG1 and RAG2 bind to and cleave at specific recombination signal sequences (RSSs) 1 generating blunt signal ends and covalently sealed, hairpin coding ends (4 -7). RSSs consist of conserved heptamer and nonamer sequences separated by a nonconserved spacer 12 or 23 base pairs long (12-and 23-RSS). V(D)J recombination occurs efficiently in vivo only between RSSs with different spacer lengths, a restriction known as the 12/23 rule (8).Recent biochemical studies indicate that V(D)J recombination proceeds through a series of protein-DNA complexes. Prior to cleavage, the RAG1 and RAG2 proteins form stable complexes with individual and synapsed pairs of RSSs (9 -17). After cleavage, the RAG proteins remain tightly bound to a synapsed pair of signal ends (15, 18) and also appear to interact with the two hairpin coding ends, albeit with lower affinity (15). Therefore, the immediate product of cleavage is thought to be a "cleaved signal complex" containing the four free ends (15).Usually, RSSs involved in V(D)J recombination are located on the same chromosome, i.e. in cis. However, V(D)J recombination has been implicated in the formation of chromosomal translocations leading to lymphoid malignancies (19 -23). In certain cases, such translocations could be the result of V(D)J recombination occurring in trans, using RSSs on different chromosomes. There have been attempts to address this issue. The first such study attempted, and fai...

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“…These generate diverse kinds of trans-rearrangements such as V␥-J␤, V␤-J␥, V␦-J␤, V␦-J␥, and V␥-J␦, (10, 17, 19 -21). Exposure of cryptic recombination signal sequence on partner chromosomes may mislead RAG proteins to rearrange interallelic gene segments (19). Nevertheless, the consistent participation of AgR loci in chromosomal translocations in lymphoma patients suggests that components of the V(D)J recombinase may participate in creating conditions for aberrant chromosomal joining (22)(23)(24) and thereby trans-rearrangements.…”

Section: The Mechanism Of Generation Of Tcr Gene Trans-rearrangementsmentioning

confidence: 99%

TCR trans-Rearrangements: Biological Significance in Antigen Recognition vs the Role as Lymphoma Biomarker

Allam

Kabelitz

2006

The Journal of Immunology

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V(D)J rearrangements occur within loci of TCR and BCR genes, thus generating the diversity of the AgR repertoire. In addition, interlocus V(D)J rearrangements occur, giving rise to so-called “trans-rearrangements.” Such trans-rearrangements increase the diversity of the immune receptor repertoire and can be expressed as functional chimeric TCR proteins on the surface of T cells. Although chimeric receptors are not pathogenic per se, the frequency of AgR trans-rearrangements correlates with the level of genetic instability and thus could be used as a predictive biomarker for lymphoma risk.

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Interallelic V(D)J trans-rearrangement within the beta T cell receptor gene is infrequent and occurs preferentially during attempted D beta to J beta joining.

Cited by 13 publications

References 38 publications

Cryptic Signals and the Fidelity of V(D)J Joining

Cryptic Signals and the Fidelity of V(D)J Joining

Intermolecular V(D)J Recombination

TCR trans-Rearrangements: Biological Significance in Antigen Recognition vs the Role as Lymphoma Biomarker

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