The Mechanism of V(D)J Joining: Lessons from Molecular, Immunological, and Comparative Analyses

Lewis, Susanna M.

doi:10.1016/s0065-2776(08)60450-2

Cited by 545 publications

(355 citation statements)

References 510 publications

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“…The recombination signal sequences consist of conserved heptamer and nonamer sequences separated by a spacer region of either 12 or 23 nucleotides. (1,14,15) The recombination signal sequences are recognized by the recombinase, the RAG-1 and RAG-2 proteins, along with HMG1. (6,7) RAG-1 and RAG-2 proteins act in concert to assemble an appropriate pair of RSSs into a synaptic complex and introduce double-strand breaks (DSBs).…”

Section: Lymphoid Translocations: An Overviewmentioning

confidence: 99%

“…Translocations that arise during the meiotic steps of gamete formation or at early stages of embryogenesis (constitutional translocations) may lead to inherited abnormalities and those that arise in somatic cells may lead to cancer (neoplastic translocations). (1,2) The double-strand breaks in such events are generated on chromosomes by exogenous agents (background ionizing radiation from cosmic or terrestrial sources) or endogenous agents (oxidative free radicals or enzymes of DNA metabolism). Ideally, such DSBs are either repaired by the cells, or the breaks lead to cell death.…”

Section: Introductionmentioning

confidence: 99%

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DNA structures at chromosomal translocation sites

Raghavan

Lieber

2006

BioEssays

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SummaryIt has been unclear why certain defined DNA regions are consistently sites of chromosomal translocations. Some of these are simply sequences of recognition by endogenous recombination enzymes, but most are not. Recent progress indicates that some of the most common fragile sites in human neoplasm assume non-B DNA structures, namely deviations from the Watson-Crick helix. Because of the single strandedness within these non-B structures, they are vulnerable to structure-specific nucleases. Here we summarize these findings and integrate them with other recent data for non-B structures at sites of consistent constitutional chromosomal translocations.

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Section: Lymphoid Translocations: An Overviewmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA structures at chromosomal translocation sites

Raghavan

Lieber

2006

BioEssays

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“…The vast number of unique antigen receptors that are produced by lymphocytes to mediate such immune responses, are encoded by the T cell receptor (TCR) and immunoglobulin (Ig) genes that are assembled from individual V, D, and J gene segments by a somatic gene rearrangement process named V(D)J recombination [reviewed in 1,2,3 ]. During lymphocyte development, the proteins encoded by the recombination activating genes 1 and 2 (RAG1 and RAG2) work in concert to generate DNA double strand breaks (DSBs) at the evolutionarily conserved recombination signal sequences (RSS) flanking each V, D, and J gene segment [reviewed in 4 ].…”

Section: Introductionmentioning

confidence: 99%

The PHD domain of the sea urchin RAG2 homolog, SpRAG2L, recognizes dimethylated lysine 4 in histone H3 tails

Wilson

Norton

Fugmann

2008

Developmental & Comparative Immunology

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V(D)J recombination is a somatic gene rearrangement process that assembles antigen receptor genes from individual segments during lymphocyte development. The access of the RAG1/RAG2 recombinase to these gene segments is regulated at the level of chromatin modifications, in particular histone tail modifications. Trimethylation of lysine 4 in histone H3 (H3K4me3) correlates with actively recombining gene elements, and this mark is recognized and interpreted by the plant homeodomain (PHD) of RAG2. Here we report that the PHD domain of the only known invertebrate homolog of RAG2, the SpRAG2L protein of the purple sea urchin (Strongylocentrotus purpuratus) also binds to methylated histones, but with a unique preference for H3K4me2. While the cognate substrate for the sea urchin RAG1L/RAG2L complex remains elusive, the affinity for histone tails and the nuclear localization of ectopically expressed SpRAG2L strongly support the model that this enzyme complex exerts its activity on DNA in the context of chromatin.

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“…The Ig and TCR loci consist of variable (V), diversity (D) and joining (J) germline coding segments that are flanked by RSSs that contain conserved heptamer and nonamer sequences separated by 12 or 23 nucleotides (Fugmann, et al, 2000;Gellert, 2002;Kim, et al, 2000;Lewis, 1994). The V(D)J recombinase activating genes 1 and 2 (RAG1/2) mediate recombination between two coding segments by introducing a single strand nick at each RSS followed by conversion to a double strand break generating four free ends.…”

Section: Introductionmentioning

confidence: 99%

“…The V(D)J recombinase activating genes 1 and 2 (RAG1/2) mediate recombination between two coding segments by introducing a single strand nick at each RSS followed by conversion to a double strand break generating four free ends. The two signal ends are excised bringing together the remaining two coding ends that are then modified and ligated by proteins of the nonhomologous end-joining pathway (Fugmann, et al, 2000;Gellert, 2002;Kim, et al, 2000;Lewis, 1994). This can result in the addition of templated (P) nucleotides, nibbling, and/or the addition of non-templated (N) nucleotides generating additional diversity at the newly formed coding joint.…”

Section: Introductionmentioning

confidence: 99%

V(D)J recombinase mediated inter-chromosomalHPRT alterations at cryptic recombination signal sequences in peripheral human T cells

2006

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The V(D)J recombinase enzyme complex is responsible for the development of a diverse immune system by catalyzing intra-molecular rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes at specific recombination signal sequences (RSSs). This enzyme complex has also been implicated in mediating pathologic and non-pathologic intra-and inter-molecular genomic rearrangements at cryptic (Ψ) RSSs outside the immune system loci in lymphoid cells. We describe here two V(D)J recombinase mediated genomic rearrangements resulting in alterations at the HPRT locus in human T-cells. These are interchromosomal insertions in which DNA fragments are inserted at breakpoints generated by V(D)J recombinase cleavage at Ψ RSS sites in the HPRT locus at Xq26. In the first, a TCR α signal ended segment from chromosome 14q11 is inserted at a Ψ RSS in intron 1 of the HPRT locus. In the second, a DNA fragment from 9q22 is integrated between the coding ends generated by a V(D)J recombinase mediated HPRT deletion. Identification of these in vivo V(D)J mediated inter-chromosomal insertions at Ψ RSSs in the HPRT gene supports the accumulating evidence that V(D)J recombinase can mediate mutagenic rearrangements in humans with potential pathologic consequences.

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The Mechanism of V(D)J Joining: Lessons from Molecular, Immunological, and Comparative Analyses

Cited by 545 publications

References 510 publications

DNA structures at chromosomal translocation sites

DNA structures at chromosomal translocation sites

The PHD domain of the sea urchin RAG2 homolog, SpRAG2L, recognizes dimethylated lysine 4 in histone H3 tails

V(D)J recombinase mediated inter-chromosomalHPRT alterations at cryptic recombination signal sequences in peripheral human T cells

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