Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation

Champ, P. Christoph; Maurice, Sandor; Vargason, J.M.; Camp, Tracy; Ho, P Shing

doi:10.1093/nar/gkh988

Cited by 74 publications

(93 citation statements)

References 27 publications

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“…It has been demonstrated that the E3L N-terminal domain binding to Z-DNA is necessary for pathogenicity in mice (8). Z-DNA-forming sequences are found near the transcription start site of many human genes (14), and negative supercoiling generated behind a moving polymerase during transcription (15) stabilizes Z-DNA formation. Z-DNA formation has been detected in the promoter region of actively transcribed genes in mammalian cells (16).…”

Section: Resultsmentioning

confidence: 99%

“…Because Z-DNA cannot form nucleosomes (30), it leaves a nucleosome-free region near the transcription start site, allowing transcription factors to be recruited, so that transcription ensues. Because most human genes have Z-DNA-forming sequences near the transcription start site (14), it is possible that E3L binding to such sequences up-regulates transcription. Further experiments are clearly necessary.…”

Section: Resultsmentioning

confidence: 99%

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Biological function of the vaccinia virus Z-DNA-binding protein E3L: Gene transactivation and antiapoptotic activity in HeLa cells

Kwon

Rich

2005

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

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The vaccinia virus (VV) E3L protein is essential for virulence and has anti-apoptotic activity. In mice, Z-DNA-binding activity of the N-terminal domain of E3L (Z␣) is necessary for viral lethality. Here, we report that inhibition of hygromycin-B-induced apoptosis in HeLa cells depends on Z-DNA binding of the E3L Z␣ domain. Z-DNA-binding domains of other proteins are equally effective in blocking apoptosis. Using a transient reporter assay, we demonstrate transactivation of human IL-6, nuclear factor of activated T cells (NF-AT), and p53 genes by E3L. This activation also requires Z-DNA binding of the N-terminal domain of E3L. Overall, this work suggests that the important role of E3L in VV pathogenesis involves modulating expression of host cellular genes at the transcriptional level and inhibiting apoptosis of host cells through Z-DNA binding.apoptosis ͉ interleukin-6 ͉ p53 ͉ poxvirus V accinia virus (VV) is a large double-stranded DNA virus encoding Ϸ190 genes, and it causes major changes in the host cell machinery shortly after infection. E3L is a host range gene, necessary for efficient VV replication in several cell lines (1) and is required for VV pathogenesis (2). The E3L gene is expressed early during infection, and the protein is present in both the nucleus and cytoplasm of infected and transfected cells. E3L accumulates in the nucleus (3), but little is known about its activities there. E3L has two domains, an N-terminal Z-DNAbinding protein domain (Z␣) and a C-terminal double-stranded RNA-binding domain (Fig. 1A). The N-terminal region is similar to the Z␣ domain of several Z-DNA-binding protein families that include the RNA editing enzyme ADAR1 (double-stranded RNA adenosine deaminase) (4), the tumor-related DLM1 (or ZBP1) protein (5), and the recently described PKR-like kinase of bony fish (6). The crystal structures of two Z␣ domains, Z␣ ADAR1 (Fig. 1B) (7) and Z␣ DLM1 (5), have shown them complexed to Z-DNA. Both N-terminal and C-terminal domains are required for infection and full pathogenesis in the mouse model (2). It has been shown that viral pathogenicity requires E3L binding to Z-DNA (8). The N-terminal half of the E3L protein is highly conserved among distantly related poxviruses, and E3L from another poxvirus has been cocrystallized with Z-DNA (9), but the functional role of this region has not been well characterized. It has been suggested that the N-terminal domain of E3L is involved in the direct inhibition of protein kinase R (PKR) activation, nuclear localization, and Z-DNA binding (8,10,11). A VV mutant lacking E3L induces apoptosis in HeLa cells (12). Furthermore, it has been reported that E3L inhibits dsRNA-induced apoptosis in NIH 3T3 cells and has some oncogenic properties (12). This suggests the possibility that E3L acts by modifying transcription, as do proteins from other DNA viruses (see Supporting Text, which is published as supporting information on the PNAS web site).In this report, we have inquired whether E3L functions as a transcriptional regulator on several genes tha...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Biological function of the vaccinia virus Z-DNA-binding protein E3L: Gene transactivation and antiapoptotic activity in HeLa cells

Kwon

Rich

2005

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

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“…The authors suggested that Z-DNA upstream of the nuclear factor-1 binding site helped to maintain the gene in its activated, nucleosome-free state (nucleosomes do not bind to the very rigid Z-DNA form (Ausio et al, 1987)). In support of its potential role in the regulation of eukaryotic genes, we have found that Z-forming sequences accumulate near the transcription start site of genes in humans and other eukaryotes (Khuu et al, 2007;Schroth et al, 1992), and that ~80% of the genes in human chromosome 22 have at least one Z-DNA sequence in the vicinity of their transcription start sites (Champ et al, 2004). The discovery of protein domains having very high specificity for Z-DNA (Rich and Zhang, 2003), in some cases with nanomolar K D 's, have suggested additional functions that include, for example, RNA editing and gene transactivation.…”

Section: Z-dnamentioning

confidence: 83%

DNA Structure: Alphabet Soup for the Cellular Soul

Ho¹,

Carter²

2011

DNA Replication-Current Advances

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“…The potential to form a Z-DNA structure also correlates with regions of active transcription. By analysis of the human chromosome 22 genomic sequence, Champ et al (2004) showed that both Z-DNAforming regions and promoter sites for nuclear factor-I correlate with the location of known and predicted genes across the chromosome and accumulate around the transcriptional start sites of the known gene. Therefore, we supposed that the insertion of the element influenced the twist gene downstream and further resulted in the mutant phenotype.…”

Section: Sequence Cloning and Nucleotide Analysismentioning

confidence: 99%

Structural analysis of a 4414-bp element in Drosophila melanogaster

Yu¹,

Wang²,

Li³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. We cloned a 4414-bp element from a mutant of Drosophila melanogaster. Its insertion site was 18,929,626 bp. Analysis of the nucleotide and amino acid sequences demonstrated that the element is homologous to Pifo_I, first obtained from D. yabuka, which belongs to the gypsy/Ty3 subfamily. We also obtained a 3754-bp length element from a wild-type fly by PCR, with a pair of primers designed from the conserved region of the 4414-bp length element. The two elements included a pair of long terminal repeats and part of the GAG and ENV proteins, but the POL protein was completely lost. This element is found in the subgenus of D. melanogaster, but it is a degenerate type of Pifo_I and is not infective. Also, a 714-bp region structured in 5.0 tandem repeats of 143 bp each was found in the 5ꞌUTR of the degenerate element; these could interact with transcription factor CF2. Phylogenetic analysis and alignment of amino acids indicated that the Pifo_I element was closer to the ZAM retrotransposon, which gave us some clues to their functional similarity. Based on these data, we propose that there is a relationship between the degenerate element

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Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation

Cited by 74 publications

References 27 publications

Biological function of the vaccinia virus Z-DNA-binding protein E3L: Gene transactivation and antiapoptotic activity in HeLa cells

Biological function of the vaccinia virus Z-DNA-binding protein E3L: Gene transactivation and antiapoptotic activity in HeLa cells

DNA Structure: Alphabet Soup for the Cellular Soul

Structural analysis of a 4414-bp element in Drosophila melanogaster

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