Z-DNA, an active element in the genome

Wang, Guliang; Vásquez, Karen M.

doi:10.2741/2399

Cited by 109 publications

(103 citation statements)

References 145 publications

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“…Non-homologous end-joining repair at DSBs in mammalian cells can result in largescale deletions, translocations and rearrangements. Adapted from [162]. The junction can be rotated and resolved to non-crossover and crossover products.…”

Section: Discussionmentioning

confidence: 99%

DNA triple helices: Biological consequences and therapeutic potential

Jain

Wang²,

Vásquez³

2008

Biochimie

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262

199

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DNA structure is a critical element in determining its function. The DNA molecule is capable of adopting a variety of non-canonical structures, including three-stranded (i.e. triplex) structures, which will be the focus of this review. The ability to selectively modulate the activity of genes is a longstanding goal in molecular medicine. DNA triplex structures, either intermolecular triplexes formed by binding of an exogenously applied oligonucleotide to a target duplex sequence, or naturally occurring intramolecular triplexes (H-DNA) formed at endogenous mirror repeat sequences, present exploitable features that permit site-specific alteration of the genome. These structures can induce transcriptional repression and site-specific mutagenesis or recombination. Triplex-forming oligonucleotides (TFOs) can bind to duplex DNA in a sequence specific fashion with high affinity, and can be used to direct DNA-modifying agents to selected sequences. H-DNA plays important roles in vivo and is inherently mutagenic and recombinogenic, such that elements of the H-DNA structure may be pharmacologically exploitable. In this review we discuss the biological consequences and therapeutic potential of triple helical DNA structures. We anticipate that the information provided will stimulate further investigations aimed toward improving DNA triplexrelated gene targeting strategies for biotechnological and potential clinical applications.

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Section: Discussionmentioning

confidence: 99%

DNA triple helices: Biological consequences and therapeutic potential

Jain

Wang²,

Vásquez³

2008

Biochimie

Self Cite

262

199

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“…concentrated near the transcription start sites (26) and have been implicated in gene regulation (27)(28)(29)(30), chromatin remodeling (31), recombination (32,33) and large-scale deletions (34). It is interesting to note that many cancer-associated genes, including EGFR, ER-a, Cyr61, ACCA, prolactin, MMP-9, heme oxygenase 1, and HMGA2, contain dinucleotide repeat elements that have been identified as regulatory elements (Supplementary Table S1); but how these sequences regulate gene expression remained poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…32 P-labeled ADAM-12 NRE DNA was used as probe. DNA probe was methylated by CpG methyltransferase (New England BioLab) following manufacturer's protocol.…”

Section: Dna-binding Assay and Western Blot Analysismentioning

confidence: 99%

Epigenetic Regulation by Z-DNA Silencer Function Controls Cancer-Associated ADAM-12 Expression in Breast Cancer: Cross-talk between MeCP2 and NF1 Transcription Factor Family

et al. 2013

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A disintegrin and metalloprotease domain-containing protein 12 (ADAM-12) is upregulated in many human cancers and promotes cancer metastasis. Increased urinary level of ADAM-12 in breast and bladder cancers correlates with disease progression. However, the mechanism of its induction in cancer remains less understood. Previously, we reported a Z-DNA-forming negative regulatory element (NRE) in ADAM-12 that functions as a transcriptional suppressor to maintain a low-level expression of ADAM-12 in most normal cells. We now report here that overexpression of ADAM-12 in triple-negative MDA-MB-231 breast cancer cells and breast cancer tumors is likely due to a marked loss of this Z-DNA-mediated transcriptional suppression function. We show that Z-DNA suppressor operates by interaction with methyl-CpG-binding protein, MeCP2, a prominent epigenetic regulator, and two members of the nuclear factor 1 family of transcription factors, NF1C and NF1X. While this tripartite interaction is highly prevalent in normal breast epithelial cells, both in vitro and in vivo, it is significantly lower in breast cancer cells. Western blot analysis has revealed significant differences in the levels of these 3 proteins between normal mammary epithelial and breast cancer cells. Furthermore, we show, by NRE mutation analysis, that interaction of these proteins with the NRE is necessary for effective suppressor function. Our findings unveil a new epigenetic regulatory process in which Z-DNA/MeCP2/NF1 interaction leads to transcriptional suppression, loss of which results in ADAM-12 overexpression in breast cancer cells. Cancer Res; 73(2); 736-44. Ó2012 AACR.

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“…Transcription can induce Z-DNA formation, and the Z-DNA structure formed at or near the promoter region of genes regulates their transcription in vivo (14, 15). Z-DNA has also been implicated in various human diseases such as blood cancers, autoimmune diseases, and Alzheimer's disease (16,17).Although the biological significance of Z-DNA has begun to be appreciated, our fundamental understanding of Z-DNA is far from complete (5). Despite the recent success in determining the structure of a B-Z-DNA junction (18), the thermodynamic and energetic details available for Z-DNA are still lacking.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Minute negative superhelicity is sufficient to induce the B-Z transition in the presence of low tension

Lee

Kim

Hong

2010

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

117

107

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Left-handed Z-DNA has fascinated biological scientists for decades by its extraordinary structure and potential involvement in biological phenomena. Despite its instability relative to B-DNA, Z-DNA is stabilized in vivo by negative supercoiling. A detailed understanding of Z-DNA formation is, however, still lacking. In this study, we have examined the B-Z transition in a short guanine/cytosine (GC) repeat in the presence of controlled tension and superhelicity via a hybrid technique of single-molecule FRET and magnetic tweezers. The hybrid scheme enabled us to identify the states of the specific GC region under mechanical control and trace conformational changes synchronously at local and global scales. Intriguingly, minute negative superhelicity can facilitate the B-Z transition at low tension, indicating that tension, as well as torsion, plays a pivotal role in the transition. Dynamic interconversions between the states at elevated temperatures yielded thermodynamic and kinetic constants of the transition. Our single-molecule studies shed light on the understanding of Z-DNA formation by highlighting the highly cooperative and dynamic nature of the B-Z transition.NA is capable of adopting various conformations in addition to the conventional right-handed B-DNA double helix (1, 2). One of the most dramatic examples is Z-DNA, which is a lefthanded helical form with a zigzag backbone (3, 4). Since its discovery, Z-DNA has drawn considerable attention from a broad range of research areas, including physical biochemistry, structural biology, and molecular biology, because of its intriguing and unusual structural features (3). The bases in Z-DNA alternate in syn-and anti-conformations while all the bases in B-DNA adopt the anti-conformation. Because the syn conformation is more stable for purines (Pu) than for pyrimidines (Py), alternating Pu and Py sequences readily adopt the Z-DNA conformation. Another striking feature of Z-DNA is the overturning of base pairs, posing a steric dilemma known as the chain sense paradox (3, 5).Although Z-DNA is less stable than B-DNA at physiological ionic conditions, Z-DNA exists stably under certain conditions such as high ionic strength or negative supercoiling (4, 6-8).In the presence of a high-salt solution, the electrostatic repulsion between the phosphate backbones, which are closer in Z-DNA than in B-DNA, is reduced, stabilizing the Z-DNA conformation. Negative supercoiling induces the Z-DNA conformation even in physiological salt conditions because formation of Z-DNA significantly relieves torsional stress. Z-DNA has also been shown to exist stably in vivo in the presence of physiological negative supercoiling (9, 10).Although there were first doubts as to whether Z-DNA plays any biological role, considerable experimental evidence for biological functions of Z-DNA has accumulated over the past two decades (11). In addition to the discovery of antibodies and proteins that bind selectively to Z-DNA (12, 13), Z-DNA formation has been strongly correlated with transcriptional acti...

show abstract

Z-DNA, an active element in the genome

Cited by 109 publications

References 145 publications

DNA triple helices: Biological consequences and therapeutic potential

DNA triple helices: Biological consequences and therapeutic potential

Epigenetic Regulation by Z-DNA Silencer Function Controls Cancer-Associated ADAM-12 Expression in Breast Cancer: Cross-talk between MeCP2 and NF1 Transcription Factor Family

Minute negative superhelicity is sufficient to induce the B-Z transition in the presence of low tension

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