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

Allam, Atef; Kabelitz, Dieter

doi:10.4049/jimmunol.176.10.5707

Cited by 15 publications

(13 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To address this question, we determined whether interchromosomal V(D)J rearrangements between the TCR␥ and TCR␤ loci, which are located on chromosomes 13 and 6, respectively, were present in RAG1-S723C mutant thymocytes using a nested PCR approach. 41 Interchromosomal trans-rearrangement is a predictor of global chromosomal translocations [41][42][43][44] and occurs at elevated frequencies in thymocytes that harbor mutations in genes that predispose to lymphoid neoplasia, including ATM, [44][45][46][47] DNA-PKcs, 41 and Nbs1. 43,44 We detected PCR products corresponding to trans-rearrangements between TCR␥V3S1 and TCR␤J2 in RAG1-S723C mutant thymocytes as well as ATM-null thymocytes ( Figure 5A).…”

Section: The Rag1-s723c Mutation Leads To Interlocus Trans-rearrangemmentioning

confidence: 99%

Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation

Giblin

Chatterji

Westfield

et al. 2009

Blood

View full text Add to dashboard Cite

The RAG1/2 endonuclease initiates programmed DNA rearrangements in progenitor lymphocytes by generating doublestrand breaks at specific recombination signal sequences. This process, known as V(D)J recombination, assembles the vastly diverse antigen receptor genes from numerous V, D, and J coding segments. In vitro biochemical and cellular transfection studies suggest that RAG1/2 may also play postcleavage roles by forming complexes with the recombining ends to facilitate DNA end processing and ligation. In the current study, we examine the in vivo consequences of a mutant form of RAG1, RAG1-S723C, that is proficient for DNA cleavage, yet exhibits defects in postcleavage complex formation and end joining in vitro. We generated a knockin mouse model harboring the RAG1-S723C hypomorphic mutation and examined the immune system in this fully in vivo setting. RAG1-S723C homozygous mice exhibit impaired lymphocyte development and decreased V(D)J rearrangements. Distinct from RAG nullizygosity, the RAG1-S723C hypomorph results in aberrant DNA double-strand breaks within rearranging loci. RAG1-S723C also predisposes to thymic lymphomas associated with chromosomal translocations in a p53 mutant background, and heterozygosity for the mutant allele accelerates age-associated immune system dysfunction. Thus, our study provides in vivo evidence that implicates aberrant RAG1/2 activity in lymphoid tumor development and premature immunosenescence. IntroductionThe immense diversity of genes encoding the variable regions of antigen receptors is generated through rearrangement of component V, D, and J segments via a cut-and-paste mechanism known as V(D)J recombination. 1 These site-specific chromosomal rearrangements are initiated in progenitor lymphocytes by the recombination activating gene 1 (RAG1) and RAG2 proteins that comprise a lymphoid-specific endonuclease, RAG1/2. 2,3 DNA double-strand breaks (DSBs) are generated by RAG1/2 at specific recombination signal sequences (RSSs) adjacent to the numerous rearranging V, D, and J coding exons. 4 The broken ends are then processed and joined by ubiquitously expressed nonhomologous end-joining (NHEJ) DNA repair factors, including Ku70, Ku80, the DNAdependent protein kinase catalytic subunit (DNA-PKcs), Artemis, DNA ligase IV, XRCC4 and Cernunnos/XLF. 1,5,6 The RAG1/2 endonuclease initially binds to RSSs that are composed of a conserved heptamer and nonamer separated by relatively nonconserved spacer sequences of either 12 or 23 nucleotides. 4 Efficient cleavage requires recombination between one 12 RSS and one 23 RSS in the context of a synaptic, paired complex mediated by RAG1/2. RAG1/2 nicks the duplex DNA at the junction between the RSS heptamer and coding sequences then uses the resulting 3Ј OH in a direct transesterification reaction with the phosphodiester backbone of the opposing strand. The products of RAG1/2 cleavage are blunt, 5Ј phosphorylated signal ends and covalently closed, hairpin coding ends. Sequence elements within the nonconserved 12 and 23 spacers 7 and coding ...

show abstract

Section: The Rag1-s723c Mutation Leads To Interlocus Trans-rearrangemmentioning

confidence: 99%

Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation

Giblin

Chatterji

Westfield

et al. 2009

Blood

View full text Add to dashboard Cite

show abstract

“…It has been suggested that the absolute number of "innocent" trans-rearrangements with both breakpoints in TCR gene loci correlates with the risk of lymphoma, regardless of whether that risk is based on an inherited predisposition or acquired exposure. An assay of trans-rearrangements may serve as a biomarker of lymphoma risk (Lipkowitz et al 1992;Lista et al 1997;Kirsch 1997;Lopes et al 2001;Allam and Kabelitz 2006). An increased number of innocent trans-rearrangements involving TRA/TRD in pigs may thus indicate a higher risk of T-cell lymphoma than in humans.…”

Section: Discussionmentioning

confidence: 98%

“…The effect of chemotherapy was transient, and the study in paediatric patients showed that higher levels were exhibited only in patients homozygous for the wild type of CYP3A4 (Lopes et al 2004). The results suggest that the absolute number of TCR trans-rearrangements may serve as a biomarker of genomic instability, genotoxic exposure and lymphoma risk (Lista et al 1997;Kirsch 1997;Allam and Kabelitz 2006).…”

Section: Introductionmentioning

confidence: 88%

Illegitimate recombination between T cell receptor genes in humans and pigs (Sus scrofa domestica)

et al. 2014

View full text Add to dashboard Cite

T cell receptor (TCR) genes (TRA/TRD, TRB and TRG) reside in three regions on human chromosomes (14q11.2, 7q34 and 7p14, respectively) and pig chromosomes (7q15.3-q21, 18q11.3-q12 and 9q21-22, respectively). During the maturation of T cells, TCR genes are rearranged by site-specific recombination. Occasionally, interlocus recombination of different TCR genes takes place, resulting in chromosome rearrangements. It has been suggested that the absolute number of these "innocent" trans-rearrangements correlates with the risk of lymphoma. The aims of this work were to assess the frequencies of rearrangements with breakpoints in TCR genes in domestic pig lymphocytes and to compare these with the frequencies of corresponding rearrangements in human lymphocytes by using fluorescence in situ hybridization with chromosome painting probes. We show that frequencies of trans-rearrangements involving TRA/TRD locus in pigs are significantly higher than the frequency of translocations with breakpoints in TRB and TRG genes in pigs and the frequencies of corresponding trans-rearrangements involving TRA/TRD locus in humans. Complex structure of the pig TRA/TRD locus with high number of potential V(D)J rearrangements compared to the human locus may account for the observed differences. Furthermore, we demonstrated that trans-rearrangements involving pig TRA/TRD locus occur at lower frequencies in γδ T cells than in αβ T lymphocytes. The decrease of the frequencies in γδ T cells is probably caused by the absence of TRA recombination during maturation of this T cell lineage. High numbers of innocent trans-rearrangements in pigs may indicate a higher risk of T-cell lymphoma than in humans.

show abstract

“…These erroneous rearrangements can result in the juxtaposition of oncogenes with TCR regulatory sequences, which are recurrent in several T cell malignancies [Boehm and Rabbitts, 1989;Korsmeyer, 1992;Marculescu et al, 2006]. It has been suggested that the absolute number of interlocus rearrangements correlates with the risk of lymphoma [Kirsch, 1997;Lista et al, 1997;Allam and Kabelitz, 2006]. A high number of trans -rearrangements in horses may thus indicate a higher risk of T cell lymphoma than in humans.…”

Section: Discussionmentioning

confidence: 99%

Impact of Karyotype Organization on Interlocus Recombination between T Cell Receptor Genes in Equidae

Drbalová

Musilová

Kubı́čková

et al. 2014

Cytogenet Genome Res

View full text Add to dashboard Cite

The T cell receptor (TCR) genes (TRA, TRB, TRD and TRG) reside in 3 different chromosomal regions. During the maturation of T lymphocytes, the TCR genes are rearranged by site-specific recombination, a process that also predisposes T cells to aberrant rearrangements. Illegitimate recombination between the TCR genes occurs at a low level in healthy individuals, but this frequency may correlate with the risk of lymphoma. The aim of this work was to investigate interlocus recombination in equids. Illegitimate rearrangements were studied in peripheral blood lymphocytes by FISH with painting and BAC probes and by sequencing of PCR products, and the frequencies of recombination were assessed in horses and 4 other equids. The presence of several trans-rearrangement products between the TRA and TRG genes was verified by PCR in all investigated equids. Frequencies of trans-rearrangements in horses are higher than in humans, and colocalization of the TCR genes on the same chromosome increases the incidence of trans-rearrangements between them. The orientation of the TCR genes does not impact interlocus recombination itself but does affect the viability of cells carrying its products and consequently the number of trans-rearrangements observed in lymphocytes.

show abstract

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

Cited by 15 publications

References 61 publications

Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation

Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation

Illegitimate recombination between T cell receptor genes in humans and pigs (Sus scrofa domestica)

Impact of Karyotype Organization on Interlocus Recombination between T Cell Receptor Genes in Equidae

Contact Info

Product

Resources

About