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Principles of nucleic acid structure
This unique and practical resource provides the most complete and concise summary of underlying principles and approaches to studying nucleic acid structure, including discussion of x-ray crystallography, NMR, molecular modelling, and databases. Its focus is on a survey of structures especially important for biomedical research and pharmacological applications. To aid novices, the book includes an introduction to technical lingo used to describe nucleic acid structure and conformations (roll, slide, twist, buckle, etc.). This completely updated edition features expanded coverage of the latest advances relevant to recognition of DNA and RNA by small molecules and proteins. In particular, the reader will find extensive new discussions on: RNA folding, ribosome structure and antibiotic interactions, DNA quadruplexes, DNA and RNA protein complexes, and short interfering RNA (siRNA). This handy guide ends with a complete list of resources, including relevant online databases and software. * Completely updated with expanded discussion of topics such as RNA folding, ribosome structure and antibiotic interactions, DNA quadruplexes, DNA and RNA protein complexes, and short interfering RNA (siRNA)* Includes a complete list of resources, including relevant online databases and software* Defines technical lingo for novices
eBook
DNA Origami with Complex Curvatures in Three-Dimensional Space
We present a strategy to design and construct self-assembling DNA nanostructures that define intricate curved surfaces in three-dimensional (3D) space using the DNA origami folding technique. Double-helical DNA is bent to follow the rounded contours of the target object, and potential strand crossovers are subsequently identified. Concentric rings of DNA are used to generate in-plane curvature, constrained to 2D by rationally designed geometries and crossover networks. Out-of-plane curvature is introduced by adjusting the particular position and pattern of crossovers between adjacent DNA double helices, whose conformation often deviates from the natural, B-form twist density. A series of DNA nanostructures with high curvature—such as 2D arrangements of concentric rings and 3D spherical shells, ellipsoidal shells, and a nanoflask—were assembled.
Journal Article
Ultra-Short DNA Fragments Undergo A-to-B Conformational Transitions Revealed by FTIR Spectroscopy
Understanding interactions between cations and DNA is essential for elucidating the structural dynamics of this fundamental biomolecule. While B-DNA is well known to dominate in long genomic DNA under physiological ionic conditions, its stability in very short DNA fragments—particularly in dilute solutions and in crude oligonucleotide preparations—has remained largely unexplored. Previous spectroscopic studies have primarily focused on long DNA, highly purified oligonucleotides, or high-salt environments, where collective polyion effects dominate. In contrast, the present results demonstrate that even in the absence of chain overlap and under low-salt conditions, Mg2+ ions efficiently stabilize the B-form by screening phosphate–phosphate electrostatic repulsion at the intrachain level. The ability to induce an A-to-B transition in crude, ultra-short DNA fragments highlights the fundamental role of divalent counterions in governing DNA conformation and establishes a lower bound for the length scale at which B-DNA can be stabilized. These findings are particularly relevant for dilute biological systems, fragmented DNA samples, and analytical protocols where short DNA fragments and low ionic strength are unavoidable.
Journal Article
Compression and self-entanglement of single DNA molecules under uniform electric field
We experimentally study the effects of a uniform electric field on the conformation of single DNA molecules. We demonstrate that a moderate electric field (∼200 V/cm) strongly compresses isolated DNA polymer coils into isotropic globules. Insight into the nature of these compressed states is gained by following the expansion of the molecules back to equilibrium after halting the electric field. We observe two distinct types of expansion modes: a continuous molecular expansion analogous to a compressed spring expanding, and a much slower expansion characterized by two long-lived metastable states. Fluorescence microscopy and stretching experiments reveal that the metastable states are the result of intramolecular self-entanglements induced by the electric field. These results have broad importance in DNA separations and single molecule genomics, polymer rheology, and DNA-based nanofabrication.
Journal Article
How DNA Coiling Enhances Target Localization by Proteins
Many genetic processes depend on proteins interacting with specific sequences on DNA. Despite the large excess of nonspecific DNA in the cell, proteins can locate their targets rapidly. After initial nonspecific binding, they are believed to find the target site by 1D diffusion (\"sliding\") interspersed by 3D dissociation/reassociation, a process usually referred to as facilitated diffusion. The 3D events combine short intrasegmental \"hops\" along the DNA contour, intersegmental \"jumps\" between nearby DNA segments, and longer volume \"excursions.\" The impact of DNA conformation on the search pathway is, however, still unknown. Here, we show direct evidence that DNA coiling influences the specific association rate of EcoRV restriction enzymes. Using optical tweezers together with a fast buffer exchange system, we obtained association times of EcoRV on single DNA molecules as a function of DNA extension, separating intersegmental jumping from other search pathways. Depending on salt concentration, targeting rates almost double when the DNA conformation is changed from fully extended to a coiled configuration. Quantitative analysis by an extended facilitated diffusion model reveals that only a fraction of enzymes are ready to bind to DNA. Generalizing our results to the crowded environment of the cell we predict a major impact of intersegmental jumps on target localization speed on DNA.
Journal Article
The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity
The classical genetic code maps nucleotide triplets to amino acids. The associated sequence composition is complex, representing many elaborations during evolution of form and function. Other genomic elements code for the expression and processing of RNA transcripts. However, over 50% of the human genome consists of widely dispersed repetitive sequences. Among these are simple sequence repeats (SSRs), representing a class of flipons, that under physiological conditions, form alternative nucleic acid conformations such as Z-DNA, G4 quartets, I-motifs, and triplexes. Proteins that bind in a structure-specific manner enable the seeding of condensates with the potential to regulate a wide range of biological processes. SSRs also encode the low complexity peptide repeats to patch condensates together, increasing the number of combinations possible. In situations where SSRs are transcribed, SSR-specific, single-stranded binding proteins may further impact condensate formation. Jointly, flipons and patches speed evolution by enhancing the functionality of condensates. Here, the focus is on the selection of SSR flipons and peptide patches that solve for survival under a wide range of environmental contexts, generating complexity with simple parts.
Journal Article
Tension induces a base-paired overstretched DNA conformation
Mixed-sequence DNA molecules undergo mechanical overstretching by approximately 70% at 60–70 pN. Since its initial discovery 15 y ago, a debate has arisen as to whether the molecule adopts a new form [Cluzel P, et al. (1996) Science 271:792–794; Smith SB, Cui Y, Bustamante C (1996) Science 271:795–799], or simply denatures under tension [van Mameren J, et al. (2009) Proc Natl Acad Sci USA 106:18231–18236]. Here, we resolve this controversy by using optical tweezers to extend small 60–64 bp single DNA duplex molecules whose base content can be designed at will. We show that when AT content is high (70%), a force-induced denaturation of the DNA helix ensues at 62 pN that is accompanied by an extension of the molecule of approximately 70%. By contrast, GC-rich sequences (60% GC) are found to undergo a reversible overstretching transition into a distinct form that is characterized by a 51% extension and that remains base-paired. For the first time, results proving the existence of a stretched basepaired form of DNA can be presented. The extension observed in the reversible transition coincides with that produced on DNA by binding of bacterial RecA and human Rad51, pointing to its possible relevance in homologous recombination.
Journal Article
Spatial recognition and semi-quantification of epigenetic events in pancreatic cancer subtypes with multiplexed molecular imaging and machine learning
Genomic alterations are the driving force behind pancreatic cancer (PC) tumorigenesis, but they do not fully account for its diverse phenotypes. Investigating the epigenetic landscapes of PC offers a more comprehensive understanding and could identify targeted therapies that enhance patient survival. In this study, we have developed a new promising methodology of spatial epigenomics that integrates multiplexed molecular imaging with convolutional neural networks. Then, we used it to map epigenetic modification levels in the six most prevalent PC subtypes. We analyzed and semi-quantified the resulting molecular data, revealing significant variability in their epigenomes. DNA and histone modifications, specifically methylation and acetylation, were investigated. Using the same technique, we examined DNA conformational changes to further elucidate the transcriptional regulatory mechanisms involved in PC differentiation. Our results revealed that the foamy-gland and squamous-differentiated subtypes exhibited significantly increased global levels of epigenetic modifications and elevated Z-DNA ratios. Overall, our findings may suggest a potentially reduced efficacy of therapeutics targeting epigenetic regulators for these subtypes. Conversely, the conventional ductal PC subtype has emerged as a promising candidate for treatment with epigenetic modulators.
Journal Article
Structure and function of CarD, an essential mycobacterial transcription factor
CarD, an essential transcription regulator in Mycobacterium tuberculosis , directly interacts with the RNA polymerase (RNAP). We used a combination of in vivo and in vitro approaches to establish that CarD is a global regulator that stimulates the formation of RNAP-holoenzyme open promoter (RPo) complexes. We determined the X-ray crystal structure of Thermus thermophilus CarD, allowing us to generate a structural model of the CarD/RPo complex. On the basis of our structural and functional analyses, we propose that CarD functions by forming protein/protein and protein/DNA interactions that bridge the RNAP to the promoter DNA. CarD appears poised to interact with a DNA structure uniquely presented by the RPo: the splayed minor groove at the double-stranded/single-stranded DNA junction at the upstream edge of the transcription bubble. Thus, CarD uses an unusual mechanism for regulating transcription, sensing the DNA conformation where transcription bubble formation initiates.
Journal Article