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"DNA Structure"
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Making the Bend: DNA Tertiary Structure and Protein-DNA Interactions
DNA structure functions as an overlapping code to the DNA sequence. Rapid progress in understanding the role of DNA structure in gene regulation, DNA damage recognition and genome stability has been made. The three dimensional structure of both proteins and DNA plays a crucial role for their specific interaction, and proteins can recognise the chemical signature of DNA sequence (“base readout”) as well as the intrinsic DNA structure (“shape recognition”). These recognition mechanisms do not exist in isolation but, depending on the individual interaction partners, are combined to various extents. Driving force for the interaction between protein and DNA remain the unique thermodynamics of each individual DNA-protein pair. In this review we focus on the structures and conformations adopted by DNA, both influenced by and influencing the specific interaction with the corresponding protein binding partner, as well as their underlying thermodynamics.
Journal Article
Replication of G Quadruplex DNA
A cursory look at any textbook image of DNA replication might suggest that the complex machine that is the replisome runs smoothly along the chromosomal DNA. However, many DNA sequences can adopt non-B form secondary structures and these have the potential to impede progression of the replisome. A picture is emerging in which the maintenance of processive DNA replication requires the action of a significant number of additional proteins beyond the core replisome to resolve secondary structures in the DNA template. By ensuring that DNA synthesis remains closely coupled to DNA unwinding by the replicative helicase, these factors prevent impediments to the replisome from causing genetic and epigenetic instability. This review considers the circumstances in which DNA forms secondary structures, the potential responses of the eukaryotic replisome to these impediments in the light of recent advances in our understanding of its structure and operation and the mechanisms cells deploy to remove secondary structure from the DNA. To illustrate the principles involved, we focus on one of the best understood DNA secondary structures, G quadruplexes (G4s), and on the helicases that promote their resolution.
Journal Article
ARTEM: a method for RNA and DNA tertiary motif identification with backbone permutations
Non-coding RNA functions are largely defined by their 3D structures, which consist of recurrent building blocks, tertiary motifs. The computational motif search problem remains largely unsolved, as standard approaches are restrained by sequence, interactions, or backbone topology. We present ARTEM 2.0, which enables automated, unrestrained searches of RNA and DNA structure databases to identify 3D motifs. We apply ARTEM for searching kink-turns, G-quadruplexes, GNRA tetraloops, and i-motifs. ARTEM outperforms existing methods and enables the discovery of novel motif variants. ARTEM opens a fundamentally new way of studying nucleic acid 3D folds and motifs and analyzing their correlations and variations.
Journal Article
Quenching of G4-DNA intrinsic fluorescence by ligands
G-quadruplex (G4) structures formed by the guanine-rich DNA regions exhibit several distinctive optical properties, including UV absorption and circular dichroism spectra. Some G4 DNA possess intrinsic UV fluorescence whose origin is not completely clear to date. In this work, we study the effect of TMPyP4 and Methylene Blue on the intrinsic fluorescence of the dimeric G4 DNA structure formed by two d(G
3
T)
4
sequences. We demonstrate that binding of the ligands results in quenching of the intrinsic fluorescence, although the conformation of the G4 DNA and its dimeric structure remain preserved. The binding sites of the ligands were suggested by the photoinduced oxidation of guanines and analysis of binding isoterms. We discuss how DNA-ligand complexes can affect the intrinsic fluorescence of G4 DNA.
Journal Article
Alternative DNA secondary structure formation affects RNA polymerase II promoter-proximal pausing in human
Background
Alternative DNA secondary structures can arise from single-stranded DNA when duplex DNA is unwound during DNA processes such as transcription, resulting in the regulation or perturbation of these processes. We identify sites of high propensity to form stable DNA secondary structure across the human genome using Mfold and ViennaRNA programs with parameters for analyzing DNA.
Results
The promoter-proximal regions of genes with paused transcription are significantly and energetically more favorable to form DNA secondary structure than non-paused genes or genes without RNA polymerase II (Pol II) binding. Using Pol II ChIP-seq, GRO-seq, NET-seq, and mNET-seq data, we arrive at a robust set of criteria for Pol II pausing, independent of annotation, and find that a highly stable secondary structure is likely to form about 10–50 nucleotides upstream of a Pol II pausing site. Structure probing data confirm the existence of DNA secondary structures enriched at the promoter-proximal regions of paused genes in human cells. Using an in vitro transcription assay, we demonstrate that Pol II pausing at HSPA1B, a human heat shock gene, is affected by manipulating DNA secondary structure upstream of the pausing site.
Conclusions
Our results indicate alternative DNA secondary structure formation as a mechanism for how GC-rich sequences regulate RNA Pol II promoter-proximal pausing genome-wide.
Journal Article
Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases
Nucleotide repeat disorders encompass more than 30 diseases, most of which show dominant inheritance, such as Huntington's disease, spinocerebellar ataxias, and myotonic dystrophies. Yet others, including Friedreich's ataxia, are recessively inherited. A common feature is the presence of a DNA tandem repeat in the disease-associated gene and the propensity of the repeats to expand in germ and in somatic cells, with ensuing neurological and frequently also neuromuscular defects. Repeat expansion is the most frequent event in these diseases; however, sequence contractions, deletions, and mutations have also been reported. Nucleotide repeat sequences are predisposed to adopt non-B-DNA conformations, such as hairpins, cruciform, and intramolecular triple-helix structures (triplexes), also known as H-DNA. For gain-of-function disorders, oligonucleotides can be used to target either transcripts or duplex DNA and in diseases with recessive inheritance oligonucleotides may be used to alter repressive DNA or RNA conformations. Most current treatment strategies are aimed at altering transcript levels, but therapies directed against DNA are also emerging, and novel strategies targeting DNA, instead of RNA, are described. Different mechanisms using modified oligonucleotides are discussed along with the structural aspects of repeat sequences, which can influence binding modes and efficiencies.
Journal Article
Duplex-specific nuclease-resistant triple-helix DNA nanoswitch for single-base differentiation of miRNA in lung cancer cells
In this work, a duplex-specific nuclease (DSN)-resistant triplex-helix DNA nanoswitch was designed for assays of single-base differentiation of the let-7a family in lung cancer cells. Initially, although a 10-bp duplex stem in the nanoswitch was cleaved to pieces, a 10-bp triplex stem was resistant to DSN. Consequently, a triple-stranded DNA structure resistant to DSN was obtained. The pH-dependent formation of the triplex structure then produced the pH-related nanoswitch/miRNA hybrid, and the metastable nanoswitch generated an obvious signal increase at pH 6.8. Surprisingly, the pH condition at 6.8 for the best nanoswitch/miRNA hybrid is consistent with the optimal DSN catalysis, which paves the way for a first-rank DSN signal amplification (DSNSA) strategy for the single-base selective capacity of the homologous let-7a family with a limit of detection of 0.26 pM. The cyclic strategy based on the DSN-mediated triplex-helix DNA nanoswitch was verified in lung cancer cell samples and exhibited better discriminatory ability without user-unfriendly nucleotide modification or extra probe-mediated assistance, showing excellent potential for application in biomedical sensing and clinical diagnosis.
Journal Article