Recombinase, chromosomal translocations and lymphoid neoplasia: Targeting mistakes and repair failures

Marculescu, Rodrig; Vanura, Katrina; Montpellier, Bertrand; Roulland, Sandrine; Le, Trang; Navarro, Jean-Marc; Jäger, Ulrich; McBlane, Fraser; Nadel, Bertrand

doi:10.1016/j.dnarep.2006.05.015

Cited by 92 publications

(116 citation statements)

References 80 publications

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“…In one model, the RAG proteins assemble a synaptic complex containing an authentic RSS and a functional cRSS in a proto-oncogene and subsequently mediate cRSS cleavage through the standard nick-hairpin mechanism. A subset of translocations involving LMO2 and TAL1, among others are thought to arise through this mechanism (4,5). Data presented here are consistent with this hypothesis, since both substrates are cleaved by the RAG proteins through a nick-hairpin mechanism in an in vitro cleavage assay.…”

Section: Discussionsupporting

confidence: 78%

“…Whereas end joining in the first model produces two joining products (the equivalent of one signal joint and one coding joint), end joining in the second scenario produces three joining products in various possible configurations. Translocations involving Hox11 and the Bcl2 major breakpoint region, among others, are thought to occur by the second model (4,5). The origin of the DNA break introduced in the proto-oncogene may or may not be RAG-mediated.…”

Section: Discussionmentioning

confidence: 99%

“…Mechanisms of cRSS Cleavage-Two general models to explain chromosomal translocations in lymphoid malignancies mediated by mistakes in V(D)J recombination have emerged from structural analysis of derivative chromosomes and functional studies of cRSSs in cell culture (4,5). In one model, the RAG proteins assemble a synaptic complex containing an authentic RSS and a functional cRSS in a proto-oncogene and subsequently mediate cRSS cleavage through the standard nick-hairpin mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…This may occur by any of several mechanisms, including mistakenly binding and cleaving a DNA sequence that resembles an authentic RSS by a standard nick-hairpin mechanism, by targeting non-B form DNA structures and cleaving them through the introduction of staggered nicks (6), by mobilizing signal ends or episomal signal joints generated after initial RSS cleavage and promoting their integration elsewhere in the genome (either by direct transposition, end donation, or trans-V(D)J recombination) (7)(8)(9)(10), or through repair failures that allow DNA breaks to become illegitimately joined to DNA ends produced by RAG-mediated cleavage at antigen receptor loci (5).…”

mentioning

confidence: 99%

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V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies

Zhang

Swanson

2008

Journal of Biological Chemistry

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To understand the molecular basis for these large differences, we investigated the binding and cleavage of these cRSSs by the RAG1/2 proteins that initiate V(D)J recombination. We find that the RAG proteins comparably bind all cRSSs tested, albeit more poorly than a consensus RSS. We show that four cRSSs that support levels of V(D)J recombination above background levels in cell culture (LMO2, TAL1, Ttg-1, and SIL) are also cleaved by the RAG proteins in vitro with efficiencies ranging from 18 to 70% of a consensus RSS. Cleavage of LMO2 and Ttg-1 by the RAG proteins can also be detected in cell culture using ligation-mediated PCR. In contrast, Hox11 and SCL are nicked but not cleaved efficiently in vitro, and cleavage at other adventitious sites in plasmid substrates may also limit the ability to detect recombination activity at these cRSSs in cell culture.The antigen binding domains of immunoglobulins and T cell receptors are encoded in germ line arrays of V, D, and J gene segments that are assembled into functional variable exons by V(D)J recombination during lymphocyte development (1). The site of recombination is directed by a recombination signal sequence (RSS) 2 that flanks each receptor gene segment and consists of a conserved heptamer (consensus 5Ј-CACAGTG-3Ј) and nonamer (consensus 5Ј-ACAAAAACC-3Ј) separated by either 12 or 23 Ϯ 1 nucleotides of more highly varied sequence. V(D)J recombination can be conceptually divided into two phases, a cleavage phase and a joining phase (2). In the cleavage phase, the lymphoid cell-specific RAG1 and RAG2 (recombination activating gene-1 and -2, respectively) proteins assemble a multiprotein synaptic complex with two RSSs (generally one 12-RSS and one 23-RSS) and introduce a DNA double strand break at each RSS between the heptamer and adjacent coding segment via a nick-hairpin mechanism to yield a blunt 5Ј-phosphorylated signal end and a coding end terminating in a covalently sealed DNA hairpin structure. In the joining phase, the signal ends are generally joined precisely to form signal joints, and the coding ends are processed and joined to form coding joints that typically contain nucleotide additions or deletions at the junction. These processes are normally mediated by components of the nonhomologous end-joining DNA repair pathway.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies

Zhang

Swanson

2008

Journal of Biological Chemistry

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“…Both chromosomal translocations are considered to arise from a similar mechanism of illegitimate repair of V(D)J recombination intermediates with recombinasemediated breaks in the IgH gene locus and doublestrand DNA breaks of different origin at the oncogene loci. 5 A recent study by Lecluse et al 6 extended this data significantly by showing that t(11;14)-positive B-cell clones with identical CyD1/ J H junctions can persist over a long period of time in the blood of healthy individuals, up to 9 years after the initial sampling. This is far longer than the average life span of normal naive B lymphocytes and suggests the presence of long-lived precursor cells, from which circulating cells are released.…”

mentioning

confidence: 94%

Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues

et al. 2012

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n‐Octylzinnverbindungen [MAK Value Documentation in German language, 2009]

2012

The MAK‐Collection for Occupational Health and Safety

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Published in the series Gesundheitsschädliche Arbeitsstoffe , Vol. 47 (2009) The article contains sections titled: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Aufnahme, Verteilung, Ausscheidung Metabolismus Erfahrungen beim Menschen Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung

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Recombinase, chromosomal translocations and lymphoid neoplasia: Targeting mistakes and repair failures

Cited by 92 publications

References 80 publications

V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies

V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies

Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues

n‐Octylzinnverbindungen [MAK Value Documentation in German language, 2009]

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