Underwound DNA under Tension: Structure, Elasticity, and Sequence-Dependent Behaviors

Sheinin, Maxim Y.; Forth, Scott; Marko, John F.; Wang, Michelle D.

doi:10.1103/physrevlett.107.108102

Cited by 96 publications

(201 citation statements)

References 35 publications

(57 reference statements)

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“…2 B, we present measurements of L e as a function of F for different fixed values of n t between n t ¼ 0 and n t ¼ À400 from left to right. These measurements were taken for bare DNA under physiological conditions, and similar measurements have been reported several times in the past (29,39,52,53). These data illustrate the effects on DNA extension of imposing turns (denaturation or plectoneme formation) or applying forces to the bead.…”

Section: Single-molecule Mt Measurementssupporting

confidence: 77%

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Salerno

Beretta

Zanchetta

et al. 2016

Biophysical Journal

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Platinum-containing molecules are widely used as anticancer drugs. These molecules exert cytotoxic effects by binding to DNA through various mechanisms. The binding between DNA and platinum-based drugs hinders the opening of DNA, and therefore, DNA duplication and transcription are severely hampered. Overall, impeding the above-mentioned important DNA mechanisms results in irreversible DNA damage and the induction of apoptosis. Several molecules, including multinuclear platinum compounds, belong to the family of platinum drugs, and there is a body of research devoted to developing more efficient and less toxic versions of these compounds. In this study, we combined different biophysical methods, including single-molecule assays (magnetic tweezers) and bulk experiments (ultraviolet absorption for thermal denaturation) to analyze the differential stability of double-stranded DNA in complex with either cisplatin or multinuclear platinum agents. Specifically, we analyzed how the binding of BBR3005 and BBR3464, two representative multinuclear platinum-based compounds, to DNA affects its stability as compared with cisplatin binding. Our results suggest that single-molecule approaches can provide insights into the drug-DNA interactions that underlie drug potency and provide information that is complementary to that generated from bulk analysis; thus, single-molecule approaches have the potential to facilitate the selection and design of optimized drug compounds. In particular, relevant differences in DNA stability at the single-molecule level are demonstrated by analyzing nanomechanically induced DNA denaturation. On the basis of the comparison between the single-molecule and bulk analyses, we suggest that transplatinated drugs are able to locally destabilize small portions of the DNA chain, whereas other regions are stabilized.

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Section: Single-molecule Mt Measurementssupporting

confidence: 77%

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Salerno

Beretta

Zanchetta

et al. 2016

Biophysical Journal

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“…A recent single-molecule mechanics study on torsionally induced melting of DNA observed the onset of melting in DNA held under large tension (up to 36 pN) at linking deficits near s z À0.05. Complete conversion of B-DNA to L-DNA is not observed until s z À1.6 (66). Similarly, in two other recent single-molecule experiments, at tensions where no plectoneme formation occurs (R1 pN), the onset of DNA melting was not observed until s z À0.02 (26,40).…”

Section: Possible Implications For Transcriptional Control Of Chromosmentioning

confidence: 54%

“…It is true that single-molecule mechanics studies demonstrate the formation of noncanonical secondary transitions when DNA is highly underwound (24,26,66). However, these experiments involve holding the DNA molecule under tension, where writhe fluctuations are strongly suppressed compared to DNA rings in free solution.…”

Section: Possible Implications For Transcriptional Control Of Chromosmentioning

confidence: 99%

Large-Scale Conformational Transitions in Supercoiled DNA Revealed by Coarse-Grained Simulation

Krajina

Spakowitz

2016

Biophysical Journal

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Topological constraints, such as those associated with DNA supercoiling, play an integral role in genomic regulation and organization in living systems. However, physical understanding of the principles that underlie DNA organization at biologically relevant length scales remains a formidable challenge. We develop a coarse-grained simulation approach for predicting equilibrium conformations of supercoiled DNA. Our methodology enables the study of supercoiled DNA molecules at greater length scales and supercoiling densities than previously explored by simulation. With this approach, we study the conformational transitions that arise due to supercoiling across the full range of supercoiling densities that are commonly explored by living systems. Simulations of ring DNA molecules with lengths at the scale of topological domains in the Escherichia coli chromosome (~10 kilobases) reveal large-scale conformational transitions elicited by supercoiling. The conformational transitions result in three supercoiling conformational regimes that are governed by a competition among chiral coils, extended plectonemes, and branched hyper-supercoils. These results capture the nonmonotonic relationship of size versus degree of supercoiling observed in experimental sedimentation studies of supercoiled DNA, and our results provide a physical explanation of the conformational transitions underlying this behavior. The length scales and supercoiling regimes investigated here coincide with those relevant to transcription-coupled remodeling of supercoiled topological domains, and we discuss possible implications of these findings in terms of the interplay between transcription and topology in bacterial chromosome organization.

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“…1, blue). Tension changes the partitioning of the negative twist between negative writhe and left-handed helices such that the slope of the extension versus twist curve for unwound DNA decreases and eventually flattens at high tension or even increases gradually as the DNA is unwound (Sheinin et al 2011) (Fig. 1, red).…”

Section: Dna Under Torsion Twists and Then Supercoilsmentioning

confidence: 99%

“…This asymmetry reflects the chirality of the double helix and is due to conformational changes in unwound DNA under tension (Leger et al 1999;Marko and Neukirch 2013). After extensive unwinding that converts the entire molecule to a left-handed form, the extension finally shrinks again as left-handed plectonemes form in left-handed DNA (Sheinin et al 2011).…”

Section: Dna Under Torsion Twists and Then Supercoilsmentioning

confidence: 99%

Supercoiling biases the formation of loops involved in gene regulation

Finzi

Dunlap

2016

Biophys Rev

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The function of DNA as a repository of genetic information is well-known. The post-genomic effort is to understand how this information-containing filament is chaperoned to manage its compaction and topological states. Indeed, the activities of enzymes that transcribe, replicate, or repair DNA are regulated to a large degree by access. Proteins that act at a distance along the filament by binding at one site and contacting another site, perhaps as part of a bigger complex, create loops that constitute topological domains and influence regulation. DNA loops and plectonemes are not necessarily spontaneous, especially large loops under tension for which high energy is required to bring their ends together, or small loops that require accessory proteins to facilitate DNA bending. However, the torsion in stiff filaments such as DNA dramatically modulates the topology, driving it from extended and genetically accessible to more looped and compact, genetically secured forms. Furthermore, there are accessory factors that bias the response of the DNA filament to supercoiling. For example, small molecules like polyamines, which neutralize the negative charge repulsions along the phosphate backbone, enhance flexibility and promote writhe over twist in response to torsion. Such increased flexibility likely pushes the topological equilibrium from twist toward writhe at tensions thought to exist in vivo. A predictable corollary is that stiffening DNA antagonizes looping and bending. Certain sequences are known to be more or less flexible or to exhibit curvature, and this may affect interactions with binding proteins. In vivo all of these factors operate simultaneously on DNA that is generally negatively supercoiled to some degree. Therefore, in order to better understand gene regulation that involves protein-mediated DNA loops, it is critical to understand the thermodynamics and kinetics of looping in DNA that is under tension, negatively supercoiled, and perhaps exposed to molecules that alter elasticity. Recent experiments quantitatively reveal how much negatively supercoiling DNA lowers the free energy of looping, possibly biasing the operation of genetic switches.

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Underwound DNA under Tension: Structure, Elasticity, and Sequence-Dependent Behaviors

Cited by 96 publications

References 35 publications

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements

Large-Scale Conformational Transitions in Supercoiled DNA Revealed by Coarse-Grained Simulation

Supercoiling biases the formation of loops involved in gene regulation

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