Promoter, enhancer and silencer elements regulate rearrangement of an immunoglobulin transgene.

Lauster, Roland; Reynaud, Claude‐Agnès; Mårtensson, Inga‐Lill; Peter, Audrey; Bucchini, Danielle; Jami, Jacques; Weill, Jean‐Claude

doi:10.1002/j.1460-2075.1993.tb06150.x

Cited by 81 publications

(58 citation statements)

References 58 publications

(77 reference statements)

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“…Furthermore, higher rates of transcription increase the rate of recombination events that are mediated by double-strand breaks (48,55). In mammalian B lymphocytes, the rate of immunoglobulin gene locus rearrangement is influenced by the presence of active transcription (4,22). Therefore, the activation of a DNA damage checkpoint upon inactivation of a temperature-sensitive allele of TAF1 may reflect a broad but not yet fully understood connection between transcription and DNA damage signaling.…”

Section: Discussionmentioning

confidence: 99%

Activation of a DNA Damage Checkpoint Response in a TAF1-Defective Cell Line

Buchmann

Skaar

DeCaprio

2004

Molecular and Cellular Biology

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Although the link between transcription and DNA repair is well established, defects in the core transcriptional complex itself have not been shown to elicit a DNA damage response. Here we show that a cell line with a temperature-sensitive defect in TBP-associated factor 1 (TAF1), a component of the TFIID general transcription complex, exhibits hallmarks of an ATR-mediated DNA damage response. Upon inactivation of TAF1, ATR rapidly localized to subnuclear foci and contributed to the phosphorylation of several downstream targets, including p53 and Chk1, resulting in cell cycle arrest. The increase in p53 expression and the G 1 phase arrest could be blocked by caffeine, an inhibitor of ATR. In addition, dominant negative forms of ATR but not ATM were able to override the arrest in G 1 . These results suggest that a defect in TAF1 can elicit a DNA damage response.The ts13 and tsBN462 cell lines have been used as model systems to study the relationship between transcription and cell cycle control. These lines were originally isolated in screens to identify cells that underwent a cell cycle arrest upon a shift in temperature from 33 to 39°C (28, 45). It was subsequently discovered that both lines contain the same point substitution mutation (G690D) in TBP-associated factor 1 (TAF1) (TAF II 250/CCG1), a key member of the TFIID complex (32,35,36). TAF1 is the largest of several TAFs, forming a scaffold between TBP and other TAFs and contributing to activated transcription (9). The ability of TAF1 to bind to TBP and other TAFs appears to be unaffected in ts13 cells shifted to the restrictive temperature (14, 37). However, TAF1 may lose the ability to bind to TBP at the cyclin D1 promoter in cells shifted to the restrictive temperature (18).TAF1 is associated with at least three enzymatic activities. The N-and C-terminal ends of TAF1 contain a kinase activity that phosphorylates RAP74, a subunit of TFIIF (12). This kinase activity appears to be unaffected by the ts13 mutation (30). The central domain of TAF1 contains a histone acetyltransferase (HAT) activity that can acetylate TFIIE␤ and histones H3 and H4 (21, 26). The ts13 and tsBN462 point mutation in TAF1 is located within the HAT domain, and a mutation of the corresponding residue in human TAF1 resulted in temperature-sensitive elimination of the HAT activity in vitro (14). TAF1 also contains an E1 and E2 ubiquitin activating and conjugating activity that participates in the monoubiquitination of histone H1 (23). It is not known whether this activity of TAF1 is affected by the ts13 and tsBN462 mutation.Since TAF1 contributes to activated transcription, loss-offunction mutations could be expected to have significant effects on the transcription profile. Surprisingly, the ts13 and tsBN462 point mutation affected the transcription of a limited set of genes, including those that encode the cyclin-dependent kinase Cdk1/Cdc2 and cyclins D1, D3, and A (44, 49, 50). The transcription of several other genes, including c-fos and c-myc, was not reduced at the restrictive tempe...

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Section: Discussionmentioning

confidence: 99%

Activation of a DNA Damage Checkpoint Response in a TAF1-Defective Cell Line

Buchmann

Skaar

DeCaprio

2004

Molecular and Cellular Biology

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“…Additional examples of RNAPII-dependent recombination have been subsequently described in yeast (21,36,50) and mammalian cells (37,57). Special mention must be made of the modulation of recombination at the immunoglobulin loci, as both V(D)J recombination (7,31,38) and class switching (15) are positively controlled by transcription.…”

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confidence: 99%

Hpr1 Is Preferentially Required for Transcription of Either Long or G+C-Rich DNA Sequences in Saccharomyces cerevisiae

Chávez

García-Rubio

Prado

et al. 2001

Molecular and Cellular Biology

107

131

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Hpr1 forms, together with Tho2, Mft1, and Thp2, the THO complex, which controls transcription elongation and genome stability in Saccharomyces cerevisiae. Mutations in genes encoding the THO complex confer strong transcription-impairment and hyperrecombination phenotypes in the bacterial lacZ gene. In this work we demonstrate that Hpr1 is a factor required for transcription of long as well as G؉C-rich DNA sequences. Using different lacZ segments fused to the GAL1 promoter, we show that the negative effect of lacZ sequences on transcription depends on their distance from the promoter. In parallel, we show that transcription of either a long LYS2 fragment or the S. cerevisiae YAT1 G؉C-rich open reading frame fused to the GAL1 promoter is severely impaired in hpr1 mutants, whereas transcription of LAC4, the Kluyveromyces lactis ortholog of lacZ but with a lower G؉C content, is only slightly affected. The hyperrecombination behavior of the DNA sequences studied is consistent with the transcriptional defects observed in hpr1 cells. These results indicate that both length and G؉C content are important elements influencing transcription in vivo. We discuss their relevance for the understanding of the functional role of Hpr1 and, by extension, the THO complex.The control of genome stability is essential to ensure maintenance of genetic information in all cells of a living organism. Dysfunction of this control causes mutations and chromosomal aberrations that can give rise to loss of gene function, cell death, or irreversible changes in the cell program.Genetic recombination is required for mitotic DNA repair and for proper meiotic chromosome segregation. In addition, it may also be responsible for processes of genetic instability. A number of animal diseases, including cancer, originate by events of mitotic recombination between repeats that lead to chromosomal aberrations (34). Several elements have been described to enhance mitotic recombination, including DNA damage, replication defects, alteration of chromatin structure, and transcriptional activity (reviewed in reference 3). Ikeda and Matsumoto (26) first described the influence of transcription on recombination showing that recombination of phage was stimulated by transcription. In yeast, the first example of transcription-associated recombination was the finding that a hotspot of ribosomal DNA (rDNA) recombination, HOT1, was dependent on RNA polymerase I-driven transcription (55, 60). Thomas and Rothstein (56) extended transcription-induced recombination to sequences transcribed by RNA polymerase II (RNAPII). Additional examples of RNAPII-dependent recombination have been subsequently described in yeast (21,36,50) and mammalian cells (37, 57). Special mention must be made of the modulation of recombination at the immunoglobulin loci, as both V(D)J recombination (7, 31, 38) and class switching (15) are positively controlled by transcription.A gene linking transcription and genome instability in Saccharomyces cerevisae is HPR1, as hpr1 mutants show both increased l...

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“…Like in the human and murine immunoglobulin light chain (IgL) loci, the chicken IgL locus contains a B cell-specific promoter and a 3 0 -enhancer [5][6][7]. A matrix attachment region (MAR) but no enhancer has been identified in the J-C intron [8], making the avian IgL more reminiscent of the Igk rather than the Igj locus.…”

Section: Introductionmentioning

confidence: 99%

“…A matrix attachment region (MAR) but no enhancer has been identified in the J-C intron [8], making the avian IgL more reminiscent of the Igk rather than the Igj locus. Furthermore, the chicken V-J intron contains a silencer and a rearrangement-activating sequence whose combined action regulates rearrangement [5,7,9]. While the recombination activation sequence is also present in the mouse, the silencer is only found in chicken, where it is thought to be required because the avian IgL locus is more compact, spanning only approximately 20 kb, placing the non-rearranged V and J elements in relatively close proximity.…”

Section: Introductionmentioning

confidence: 99%

The chicken Ig light chain 3′‐enhancer is essential for gene expression and regulates gene conversion via the transcription factor E2A

Conlon

Meyer

2005

Eur J Immunol

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Expression of the rearranged chicken immunoglobulin light chain (IgL) gene is regulated by a V gene promoter, a matrix attachment region (MAR) in the J‐C intron and an enhancer downstream of the Ig constant region. Using knockout analysis, we demonstrate that the 3′‐enhancer is not only required for gene activation but is also essential for the maintenance of gene expression. Deletion of the MAR on the other hand increases IgL transcription, indicating that the MAR acts as negative regulator. We demonstrate that Id1 and Id3, dominant‐negative regulators of basic‐region helix‐loop‐helix (bHLH) transcription factors, are able to reduce chicken IgL 3′‐enhancer activity in transient assays and strongly reduce the rate of gene conversion (GC) in DT40 clone 18 cells. Conversely, overexpression of avian E47, a bHLH transcription factor, leads to a dramatic increase in GC rates independent of IgL or activation‐induced cytidine deaminase RNA levels. Thus, E47 is the first transcription factor to activate GC without an apparent increase in transcription.

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Promoter, enhancer and silencer elements regulate rearrangement of an immunoglobulin transgene.

Cited by 81 publications

References 58 publications

Activation of a DNA Damage Checkpoint Response in a TAF1-Defective Cell Line

Activation of a DNA Damage Checkpoint Response in a TAF1-Defective Cell Line

Hpr1 Is Preferentially Required for Transcription of Either Long or G+C-Rich DNA Sequences in Saccharomyces cerevisiae

The chicken Ig light chain 3′‐enhancer is essential for gene expression and regulates gene conversion via the transcription factor E2A

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