Inversions Produced during V(D)J Rearrangement at <i>IgH</i>, the Immunoglobulin Heavy-Chain Locus

Sollbach, A E; Wu, Gillian E.

doi:10.1128/mcb.15.2.671

Cited by 36 publications

(24 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When amplifying normal thymus DNA, consistent detection of all three types of hybrid joints required using 500 ng thymus DNA in each amplification. This is in good agreement with previous studies demonstrating that hybrid rearrangements at endogenous loci occur 100-to 1000-fold less frequently than standard rearrangements (53,54). Relative frequencies of the three different hybrid joints varied considerably in SCID thymocytes.…”

Section: Hybrid Joints Are Less Diminished In Scid Thymocytes Than Stsupporting

confidence: 82%

“…The frequency of hybrid joining, as assessed using extrachromosomal substrates, has been estimated at 10 -30% the rate of standard joining (52). The frequency of hybrid rearrangements of endogenous immune receptor gene segments is considerably lower, 100-to 1000-fold less than standard joining depending on the specific rearrangements analyzed (53,54). In 1997, Han et al made the observation that the capacity of Ku80-deficient cell lines to support RAG-induced hybrid joining of an extrachromosomal recombination substrate was similar to that observed in normal cell lines (55).…”

Section: Hybrid Joints Are Less Diminished In Scid Thymocytes Than Stmentioning

confidence: 99%

See 1 more Smart Citation

Analyses of TCRB Rearrangements Substantiate a Profound Deficit in Recombination Signal Sequence Joining in SCID Foals: Implications for the Role of DNA-Dependent Protein Kinase in V(D)J Recombination

Shin

Rijkers

Pastink

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

We reported previously that the genetic SCID disease observed in Arabian foals is explained by a defect in V(D)J recombination that profoundly affects both coding and signal end joining. As in C.B-17 SCID mice, the molecular defect in SCID foals is in the catalytic subunit of the DNA-dependent protein kinase (DNA-PKCS); however, in SCID mice, signal end resolution remains relatively intact. Moreover, recent reports indicate that mice that completely lack DNA-PKCS also generate signal joints at levels that are indistinguishable from those observed in C.B-17 SCID mice, eliminating the possibility that a partially active version of DNA-PKCS facilitates signal end resolution in SCID mice. We have analyzed TCRB rearrangements and find that signal joints are reduced by ∼4 logs in equine SCID thymocytes as compared with normal horse thymocytes. A potential explanation for the differences between SCID mice and foals is that the mutant DNA-PKCS allele in SCID foals inhibits signal end resolution. We tested this hypothesis using DNA-PKCS expression vectors; in sum, we find no evidence of a dominant-negative effect by the mutant protein. These and other recent data are consistent with an emerging consensus: that in normal cells, DNA-PKCS participates in both coding and signal end resolution, but in the absence of DNA-PKCS an undefined end joining pathway (which is variably expressed in different species and cell types) can facilitate imperfect signal and coding end joining.

show abstract

Section: Hybrid Joints Are Less Diminished In Scid Thymocytes Than Stsupporting

confidence: 82%

Section: Hybrid Joints Are Less Diminished In Scid Thymocytes Than Stmentioning

confidence: 99%

Analyses of TCRB Rearrangements Substantiate a Profound Deficit in Recombination Signal Sequence Joining in SCID Foals: Implications for the Role of DNA-Dependent Protein Kinase in V(D)J Recombination

Shin

Rijkers

Pastink

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The frequency of hybrid rearrangements of endogenous immune receptor gene segments has been shown to be ϳ100-to 1000-fold less than standard joining depending on the specific rearrangements analyzed (42,43). It has recently been shown that hybrid rearrangements can be mediated solely by the RAG proteins in a reversal of the normal cleavage reaction (44,45).…”

Section: Hybrid Joints Are Modestly Reduced In Scid Puppiesmentioning

confidence: 99%

SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency

Meek

Kienker

Dallas

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

We recently described the incidence of a SCID disease in a litter of Jack Russell terriers. In this study, we show that the molecular defect in these animals is faulty V(D)J recombination. Furthermore, we document a complete deficit in DNA-dependent protein kinase activity that can be explained by a marked diminution in the expression of the catalytic subunit DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We conclude that as is the case in C.B-17 SCID mice and in Arabian SCID foals, the defective factor in these SCID puppies is DNA-PKcs. In mice, it has been clearly established that DNA-PKcs deficiency produces an incomplete block in V(D)J recombination, resulting in “leaky” coding joint formation and only a modest defect in signal end ligation. In contrast, DNA-PKcs deficiency in horses profoundly blocks both coding and signal end joining. Here, we show that although DNA-PKcs deficiency in canine lymphocytes results in a block in both coding and signal end joining, the deficit in both is intermediate between that seen in SCID mice and SCID foals. These data demonstrate significant species variation in the absolute necessity for DNA-PKcs during V(D)J recombination. Furthermore, the severity of the V(D)J recombination deficits in these three examples of genetic DNA-PKcs deficiency inversely correlates with the relative DNA-PK enzymatic activity expressed in normal fibroblasts derived from these three species.

show abstract

“…We used seminested and nested PCR primers to analyze D ␤1 J ␤1 , D ␤1 J ␤2 , and D ␤2 J ␤2 recombination at the T-cell receptor beta (TCR␤) locus (85). Immunoglobulin heavy-chain (IgH) DJ recombination was determined using degenerate PCR primers as described previously (73).…”

Section: Genotypingmentioning

confidence: 99%

DNA Methyltransferase Deficiency Modifies Cancer Susceptibility in Mice Lacking DNA Mismatch Repair

Trinh¹,

Long²,

Nickel³

et al. 2002

Molecular and Cellular Biology

View full text Add to dashboard Cite

We have introduced DNA methyltransferase 1 (Dnmt1) mutations into a mouse strain deficient for the Mlh1 protein to study the interaction between DNA mismatch repair deficiency and DNA methylation. Mice harboring hypomorphic Dnmt1 mutations showed diminished RNA expression and DNA hypomethylation but developed normally and were tumor free. When crossed to Mlh1 ؊/؊ homozygosity, they were less likely to develop the intestinal cancers that normally arise in this tumor-predisposed, mismatch repair-deficient background. However, these same mice developed invasive T-and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wild-type littermates. Thus, the reduction of Dnmt1 activity has significant but opposing outcomes in the development of two different tumor types. DNA hypomethylation and mismatch repair deficiency interact to exacerbate lymphomagenesis, while hypomethylation protects against intestinal tumors. The increased lymphomagenesis in Dnmt1 hypomorphic, Mlh1 ؊/؊ mice may be due to a combination of several mechanisms, including elevated mutation rates, increased expression of proviral sequences or proto-oncogenes, and/or enhanced genomic instability. We show that CpG island hypermethylation occurs in the normal intestinal mucosa, is increased in intestinal tumors in Mlh1 ؊/؊ mice, and is reduced in the normal mucosa and tumors of Dnmt1 mutant mice, consistent with a role for Dnmt1-mediated CpG island hypermethylation in intestinal tumorigenesis.

show abstract

Inversions Produced during V(D)J Rearrangement at IgH, the Immunoglobulin Heavy-Chain Locus

Cited by 36 publications

References 42 publications

Analyses of TCRB Rearrangements Substantiate a Profound Deficit in Recombination Signal Sequence Joining in SCID Foals: Implications for the Role of DNA-Dependent Protein Kinase in V(D)J Recombination

Analyses of TCRB Rearrangements Substantiate a Profound Deficit in Recombination Signal Sequence Joining in SCID Foals: Implications for the Role of DNA-Dependent Protein Kinase in V(D)J Recombination

SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency

DNA Methyltransferase Deficiency Modifies Cancer Susceptibility in Mice Lacking DNA Mismatch Repair

Contact Info

Product

Resources

About