Illegitimate recombination generates a class switch from C mu to C delta in an IgD-secreting plasmacytoma.

Gilliam, A C; Shen, Anna L.; Richards, Julia E.; Blattner, Frederick R.; Mushinski, J. Frederic; Tucker, Philip W.

doi:10.1073/pnas.81.13.4164

Cited by 35 publications

(19 citation statements)

References 49 publications

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“…This implies that the deletions of C8 domains in these three hybridomas had occurred in the spleen and not during the generation of the hybridomas. (6,17). This hypothesis was correct except for KWD2 and KWD5 (see below).…”

Section: Methodsmentioning

confidence: 85%

“…Instead, it has been considered an example of illegitimate, or nonhomologous, recombination (17). Random integration is one form of illegitimate recombination which occurs so readily in mammalian cells that transfected DNA, even with a very long (3-to 10-kbp) homology to its target, is 100 to 10,000 times more likely to be randomly integrated than to undergo homologous integration (29,58 A switch recombination model.…”

Section: Discussionmentioning

confidence: 99%

“…The novel sequences of the switch recombination sites were submitted to GenBank and were assigned accession numbers M64557 through M64566. The sequence of the TEPC 1017 switch recombination site, which was previously published (17), has accession number K02150. RESULTS RNA analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Like 2C8, the other C57BL/6 hybridoma, B1-8.81 had an insert (six bases) between the 5' and 3' recombination-deletion breakpoints instead of a short homology. junction sequence in TEPC 1017 has already been reported (17) and is included in Fig. 4 and 5 to complete the list of switch recombinations involved in IgD secretion.…”

Section: ---------Ggaacaatgac---a--gg---att-t-gtg-ga-a-ca 5'germ Linementioning

confidence: 99%

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Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Owens¹,

Finkelman²,

Mountz³

et al. 1991

Mol. Cell. Biol.

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Plasma cells secrete immunoglobulins other than immunoglobulin M (IgM) after a deletion and recombination in which a portion of the immunoglobulin heavy-chain locus (IgH), from the 5'-flanking region of the ,u constant-region gene (C,e) to the 5'-flanking region of the secreted heavy-chain constant-region gene (CH), is deleted. The recombination step is believed to be targeted via switch regions, stretches of repetitive DNA which lie in the 5' flank of all CH genes except 8. Although serum levels of IgD are very low, particularly in the mouse, IgD-secreting plasmacytomas of BALB/c and C57BL/6 mice are known. In an earlier study of two BALB/c IgD-secreting hybridomas, we reported that both had deleted the C,, gene, and we concluded that this deletion was common in the normal generation of IgD-secreting cells. To learn how such switch recombinations occur in the absence of a switch region upstream of the Cr,1 exon, we isolated seven more BALB/c and two C57BL/6IgD-secreting hybridomas. We determined the DNA sequences of the switch recombination junctions in eight of these hybridomas as well as that of the C57BL/6 hybridoma B1-8.81 and of the BALB/c, IgD-secreting plasmacytoma TEPC 1033. All of the lines had deleted the C, gene, and three had deleted the C,,, exon in the switch recombination event. The delta switch recombination junction sequences were similar to those of published productive switch recombinations occurring 5' to other heavy-chain genes, suggesting that nonhomologous, illegitimate recombination is utilized whenever the heavy-chain switch region is involved in recombination. The switch from ,u, the 5'-most heavy-chain constantregion gene, to other heavy-chain classes is accomplished by another somatic rearrangement of the heavy-chain locus, the switch recombination. In switch recombination, a 5' breakpoint upstream of the C,, gene is joined to a 3' breakpoint upstream of another CH gene, and the intervening DNA is deleted. The switch recombination has been linked to switch regions: 2 to 5 kb of tandem repeats in which the tetramers AGCT and TGGG occur frequently (46). Switch regions are found in the 5'-flanking area of each CH gene except C6. Curiously, most switch recombinations do not have their 5' breakpoints in the switch ,u region (S,,), though the 3' breakpoints usually are in the switch region of the expressed CH gene (25). Since IgD is rare in human serum and very rare in mouse serum, it was believed that normal production of secreted * Corresponding author. Synthesis of immunoglobulin (IgIgD might not require switch recombination but might occur by alternative splicing of transcripts spanning the VH-D-JH and C -C. locus, the same mechanism utilized for membrane IgD (reviewed in reference 6). Although human B cells with intact C,, genes can synthesize small but significant amounts of mRNA for secreted 8 chain (30), this is not the case in mice (15). It is likely that secretion of large amounts of IgD requires some sort of recombination, since three cultured human cell lines and three human m...

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Section: Methodsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: ---------Ggaacaatgac---a--gg---att-t-gtg-ga-a-ca 5'germ Linementioning

confidence: 99%

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Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Owens¹,

Finkelman²,

Mountz³

et al. 1991

Mol. Cell. Biol.

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“…5) but to a 5.6-kb HindIlI fragment in germ line DNA (data not shown). (The two additional bands detected with H3.5 in these experiments are derived from the "unexpressed" copy of chromosome 12 and are discussed below.) As shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Independent immunoglobulin class-switch events occurring in a single myeloma cell line.

Eckhardt¹,

Birshtein²

1985

Mol. Cell. Biol.

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Five gamma 2a-producing cell lines, all derived from the gamma 2b-producing mouse myeloma MPC11, were analyzed for changes in gene structure. Also examined was a cell line (ICR9.7.1) that acts as an intermediate to some of these class switches. All six of the MPC11 variants have undergone DNA rearrangement. Rearrangement sites in the gamma 2a-producing cells are different in each case and generally do not involve tandem repeat sequences. An enhancer for heavy chain gene transcription was deleted in at least one of these cell lines as a result of its class-switch rearrangement. DNA sequence analysis of cloned genes from two of the MPC11 variants revealed shared sequences at their rearrangement breakpoints. The same sequences are found at the breakpoints of two additional immunoglobulin gene rearrangements in MPC11.

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Class switch from μ to δ is mediated by homologous recombination between σ_μ and σ_μ sequences in human immunoglobulin gene loci

Yasui

Akahori

Hirano³

et al. 1989

Eur J Immunol

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Class switch of immunoglobulin from mu to gamma occurs by recombination between two repetitive switch sequences: S mu and S gamma. However, there are no such sequences in the mu-delta introns of human and mouse genomes. Although the frequency of IgD-secreting cells is extremely low in mouse about 1% of patients with myeloma produce IgD in human. In a previous report (Nucleic Acids Res. 1988. 16: 9497) we reported that a 442-bp DNA sequence located in the JH-mu intron (defined as sigma mu) was inserted into the mu-delta intron (defined as sigma mu) in human genome. There is no such insertion in mouse. We analyzed Ig H chain gene loci of two human IgD myelomas: one was analyzed by cloning and sequencing and the other by Southern hybridization. We found that recombination had occurred between these two homologous DNA sequences, resulting in loss of the DNA segment from sigma mu to sigma mu. On the other hand, in a Burkitt lymphoma, Daudi, the DNA fragment from sigma mu to sigma mu was duplicated. These results suggest that homologous recombination between sigma mu and sigma mu sequences mediates class switch from mu to delta in human and that it occurs via unequal crossing-over between sister chromatids or daughter chromosomes.

show abstract

Illegitimate recombination generates a class switch from C mu to C delta in an IgD-secreting plasmacytoma.

Abstract: We present here the sequence characteriza-

Cited by 35 publications

References 49 publications

Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Independent immunoglobulin class-switch events occurring in a single myeloma cell line.

Class switch from μ to δ is mediated by homologous recombination between σ_μ and σ_μ sequences in human immunoglobulin gene loci

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Illegitimate recombination generates a class switch from C mu to C delta in an IgD-secreting plasmacytoma.

Abstract: We present here the sequence characteriza-

Cited by 35 publications

References 49 publications

Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Independent immunoglobulin class-switch events occurring in a single myeloma cell line.

Class switch from μ to δ is mediated by homologous recombination between σμ and σμ sequences in human immunoglobulin gene loci

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Class switch from μ to δ is mediated by homologous recombination between σ_μ and σ_μ sequences in human immunoglobulin gene loci