T cell receptor β gene sequences in the circular DNA of thymocyte nuclei: Direct evidence for intramolecular DNA deletion in V-D-J joining

Okazaki, Kenji; Davis, Donald D.; Sakano, Hitoshi

doi:10.1016/0092-8674(87)90450-8

Cited by 141 publications

(72 citation statements)

References 40 publications

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“…Such mechanisms may have been retained in evolution to enable ecient responses to selective environmental pressures, as well as to the changing requirements of dierent tissues and cells in the developing organism. This population of molecules may be either functionally important in itself or a byproduct of other processes (such as the V-D-J recombination in lymphocytes, Fujimoto et al, 1985Fujimoto et al, , 1987Okazaki et al, 1987).…”

Section: Exposure Of Normal Human ®Broblasts To Carcinogen Results Inmentioning

confidence: 99%

Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability

1997

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Section: Exposure Of Normal Human ®Broblasts To Carcinogen Results Inmentioning

confidence: 99%

Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability

1997

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“…Reciprocal products of TCR V3-D-JI gene segment recombination have been detected in the circular DNA fraction isolated from mouse thymocyte nuclei (28). Similarly, TCR a and S gene segment DRPs have been characterized (29).…”

Section: Discussionmentioning

confidence: 98%

Corrective recombination of mouse immunoglobulin kappa alleles in Abelson murine leukemia virus-transformed pre-B cells.

Feddersen¹,

Ness²

1990

Mol. Cell. Biol.

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Previous characterization of mouse immunoglobulin K gene rearrangement products cloned from murine plasmacytomas has indicated that two recombination events can take place on a single K allele (R. M. Feddersen and B. G. Van Ness, Proc. Natl. Acad. Sci. USA 82:4792-4797, 1985; M. A. Shapiro and M. Weigert, J. Immunol. 139:3834-3839, 1987). To determine whether multiple recombinations on a single K allele can contribute to the formation of productive V-J genes through corrective recombinations, we have examined several Abelson murine leukemia virus-transformed pre-B-cell clones which rearrange the K locus during cell culture. Clonal cell lines which had rearranged one K allele nonproductively while maintaining the other allele in the germ line configuration were grown, and secondary subclones, which subsequently expressed K protein, were isolated and examined for further K rearrangement. A full spectrum of rearrangement patterns was observed in this sequential cloning, including productive and nonproductive recombinations of the germ line allele and secondary recombinations of the nonproductive allele. The results show that corrective V-J recombinations, with displacement of the nonproductive K gene, occur with a significant frequency (6 of 17 K-producing subclones). Both deletion and maintenance of the primary (nonfunctional) V-J join, as a reciprocal product, were observed.The expression of immunoglobulin by B cells is dependent on gene segment rearrangements which are unique to lymphoid development (41). Highly conserved, site-specific sequences flanking variable (V) and joining (J) gene segments of the kappa (K) light-chain locus direct the complex enzymology required for DNA cutting and ligation (2). In addition to the functional products generated from rearrangement of the K locus, many defective products have been observed (3,7,10,12,14,15,19,27,30,32,36,40,43,44). In fact, from both plasmacytomas and normal B cells it has been estimated that more than one-third of all K rearrangement events are aberrant (11). Collectively, these aberrant rearrangements have suggested that clonal selection may actually mask an otherwise inefficient rearrangement process.In addition to functional and nonfunctional K transcription units, Southern blot hybridization analyses, coupled with cloning and sequencing, have identified reciprocal products of VK-JK recombination (13, 21-23, 37, 39, 42). These byproducts of V-J joining events are characterized by the back-to-back fusion of the recombination signal sequences (the conserved heptamers and nonamers) that border the germ line gene segments. The characterization of reciprocal products supports the intrastrand DNA inversion mechanism of V-J recombination. We and others (12, 38) previously characterized additional products of K locus recombination in mouse plasmacytomas. These novel elements were shown to contain a VK-JK rearrangement followed by the reciprocal element of another VK-JK rearrangement. We designated these double recombination products (DRPs). Significantly, it a...

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“…The joining of coding ends often is accompanied by nucleotide addition or trimming, leading to imprecise coding joints and further TCR diversity (3,11). The joining of the two RSS ends is precise and results in the formation of a circular episome (5,12). The excised DNA circles derived by TCR rearrangement initially were thought to be degraded rapidly in the cells in which they are generated, and their detection in T cells therefore was considered an indication of in situ TCR gene rearrangement (13).…”

mentioning

confidence: 99%

T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool

Kong

Chen

Six

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

151

118

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Progenitor cells undergo T cell receptor (TCR) gene rearrangements during their intrathymic differentiation to become T cells. Rearrangements of the variable (V), diversity (D),During their intrathymic T cell differentiation in birds and mammals, thymocyte progenitors undergo a complex series of developmental events that can be monitored by the sequential gene rearrangement and acquisition of cell surface differentiation markers (1, 2). The genes that encode the variable regions of the T cell receptor (TCR)-␣, -␤, -␥, and -␦ chains are assembled through recombination of the variable (V), diversity (D), and joining (J) gene segments (3). V(D)J recombination is initiated by the recognition of recombination signal sequences (RSS) that immediately flank the coding segments and consist of conserved heptamer and nonamer sequences separated by a nonconserved spacer of 12 or 22͞23 bp (4, 5). The lymphocyte-specific recombinase-activating gene products, RAG-1 and RAG-2, work together to recognize the RSS and introduce site-specific cleavages at the signal-coding borders of a given pair of coding segments (6, 7). The cleavage occurs on both strands of DNA, generating two types of ends: blunt signal ends and covalently sealed coding ends. The ubiquitously expressed DNA repair machinery of the cell is then recruited to complete the reaction (8-10). The joining of coding ends often is accompanied by nucleotide addition or trimming, leading to imprecise coding joints and further TCR diversity (3, 11). The joining of the two RSS ends is precise and results in the formation of a circular episome (5, 12). The excised DNA circles derived by TCR rearrangement initially were thought to be degraded rapidly in the cells in which they are generated, and their detection in T cells therefore was considered an indication of in situ TCR gene rearrangement (13). A more recent analysis of the rearrangement status of the TCR-␣͞␦ locus, which indicated the presence of excised chromosomal DNA in murine thymocytes and mature T cells, suggested that TCR DNA deletion circles could be relatively stable (14).Evidence favoring the idea that T cells can be generated in extrathymic sites has been obtained in mice (15-17) and humans (18,19), whereas the thymus appears to be the sole source of T cells in birds (20)(21)(22)(23). In the chicken, we observed an enrichment of the TCR deletion circles in recent T cell emigrants marked by their transient expression of the chT1 thymocyte antigen (23). The levels of chT1 ϩ T cells in the periphery declined in parallel with age-related thymic involution, and these cells disappeared completely after early thymectomy. The numbers of chT1 ϩ T cells in the circulation were found to correlate directly with the functional thymic mass. The chT1 antigen thus provides a convenient marker for recent thymic emigrants in birds.Because a cell surface marker for recent thymic emigrants in mammals has not been identified, the present experiments exploited the chicken model system to determine whether or not the TCR de...

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T cell receptor β gene sequences in the circular DNA of thymocyte nuclei: Direct evidence for intramolecular DNA deletion in V-D-J joining

Cited by 141 publications

References 40 publications

Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability

Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability

Corrective recombination of mouse immunoglobulin kappa alleles in Abelson murine leukemia virus-transformed pre-B cells.

T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool

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