Nucleic acid double helix

Summary

In molecular biology, the term double helix refers to the structure formed by double-stranded molecules of nucleic acids such as DNA. The double helical structure of a nucleic acid complex arises as a consequence of its secondary structure, and is a fundamental component in determining its tertiary structure. The term entered popular culture with the publication in 1968 of The Double Helix: A Personal Account of the Discovery of the Structure of DNA by James Watson. The DNA double helix biopolymer of nucleic acid is held together by nucleotides which base pair together. In B-DNA, the most common double helical structure found in nature, the double helix is right-handed with about 10–10.5 base pairs per turn. The double helix structure of DNA contains a major groove and minor groove. In B-DNA the major groove is wider than the minor groove. Given the difference in widths of the major groove and minor groove, many proteins which bind to B-DNA do so through the wi

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Identification and characterisation of small-molecule inhibitors targeting STING

Simone Margret Haag

The recognition of pathogen-derived nucleic acids is a critical mechanism by which the innate immune system detects viral infection. Upon activation, nucleic acid sensors initiate the expression of type I interferons and other inflammatory mediators, subsequently leading to potent antiviral immune responses. However, erroneous detection of nucleic acids can have deleterious consequences for the host by inducing the development of certain autoinflammatory disorders. Inappropriate sensing of self- nucleic acids underlies a spectrum of monogenic disease referred to as type interferonopathies, including the Aicardi-Goutières syndrome (AGS). These disorders are often driven by mutations in genes encoding for components of nucleic acid recognition pathways, thereby resulting in the constitutive activation of type I interferon responses. Insight into the molecular pathology of AGS has highlighted promising new targets that may be harnessed for the development of novel therapeutics to counter this disorder. Stimulator of interferon genes (STING) - a central adaptor of the cytosolic DNA sensing pathway - has been strongly implicated in the pathogenesis of distinct inflammatory disorders, including AGS. Therefore, pharmacological inhibition of STING presents a promising approach for the development of potent treatment strategies against these and potentially other STING-mediated, autoinflammatory diseases. Performing a cell-based small-molecule screen, we identified and characterized two series of compounds, which potently and selectively inhibit STING through a mechanism that blocks the activation-induced palmitoylation of STING. The identified small-molecules mediate this inhibition through covalent binding to a transmembrane predicted cysteine residue (Cys91) - a palmitoylation site required for STING activation. Using the inhibitors, we show that the palmitoylation of STING mediates the formation of multimeric complexes at the Golgi and the subsequent recruitment and activation of the direct downstream kinase TBK1. We also provide evidence that representatives of both identified compound classes potently inhibit STING-induced expression of inflammatory cytokines including type I interferon, in human and mouse cells. Furthermore, we also demonstrate that the identified STING inhibitors attenuate autoinflammatory disease features in a mouse model of AGS. Taken together, this work uncovers a small-molecule mediated mechanism to inhibit STING and demonstrates the pharmacological potential of targeting STING for the treatment of type I interferon driven disease such as AGS.

EPFL2019

Super-resolution fight club: assessment of 2D and 3D single-molecule localization microscopy software

Anurag Agrawal, Anna Archetti, Silvia Colabrese, Ricardo Henriques, Seamus John Holden, Tomas Lukes, Thomas Pengo, Thanh-An Michel Pham, Daniel Sage, Michaël Unser

With the widespread uptake of two-dimensional (2D) and three-dimensional (3D) single-molecule localization microscopy (SMLM), a large set of different data analysis packages have been developed to generate super-resolution images. In a large community effort, we designed a competition to extensively characterize and rank the performance of 2D and 3D SMLM software packages. We generated realistic simulated datasets for popular imaging modalities-2D, astigmatic 3D, biplane 3D and double-helix 3D-and evaluated 36 participant packages against these data. This provides the first broad assessment of 3D SMLM software and provides a holistic view of how the latest 2D and 3D SMLM packages perform in realistic conditions. This resource allows researchers to identify optimal analytical software for their experiments, allows 3D SMLM software developers to benchmark new software against the current state of the art, and provides insight into the current limits of the field.

2019

DNA is a long polymer with the form of a double helix of about two nanometers diameter (2.10-9 meters). It is composed of nucleotides whose sequence carries the information of heredity. The four possible nucleotides have slightly different geometries, and their sequence along the DNA molecule are thought to influence the shape and the stiffness of the double helix on a scale of few tens to a few hundred base pairs, and thereby its biological activity. DNA minicircles (or miniplasmids) are closed loops with lengths of the order of a few tens or hundreds of base pairs in which the double helix bends around to close on its own tail with some number of twists. Its minimal energy shape and its energy of formation depend on the sequence of base pairs, and can be efficiently computed by polymer and rod models, if shape and stiffness parameters of DNA are provided as inputs. This structure is therefore an interesting experimental motif to test sequence-dependent mechanical properties of the DNA molecule. The purpose of this thesis is to explore the experimental methods to determine the shape and free energy of formation of DNA minicircles. The shapes have been be determined from cryo-electron micrographs. Efficiency of formation has been investigated by a novel method called annealing-cyclization. Cryo-electron microscopy allows observation of very small molecules (here 17 or 11 nm diameter) in vitrified water, in order to keep the 3D shape of the molecules as close as possible to the shape they had in solution. In Chapter 1, I used stereo cryo-electron micrographs to determine and compare the three-dimensional shape of 95 individual DNA minicircles of 158 base pairs, which were identical in sequence except within a 18 bp block which contained either a TATA box sequence or a CAP site. I defined the notion of shape-distance which I used to estimate the error of reconstruction, and I detected clusters of shapes using an appropriate sorting algorithm. However the cluster did not seem to be associated with the variable sequence (TATA or CAP). I then analyzed (in Chapter 2) two-dimensional shapes of shorter DNA minicircles (94 bp) determined by negative staining electron microscopy, designed with either two nicks (breaks in one of the strands) or two gaps (missing nucleotides) at diametrically opposite sites of the minicircles. I observed that the gapped minicircles have an elongated shape with respect to the nicked minicircles, and I used this result together with the results of atomic level molecular dynamics simulations to conclude that the gap flexibility, perhaps together with base unpairing at the gap site, is responsible for this elongated minicircle shape. Finally, I proposed a ligase-free assay to measure the minicircle formation efficiency, which can give a high yield of nicked minicircles. The method avoids the use of ligase and the associated concerns about the effect of ligase concentration on the measurements. I determined an equation from a chemical model of the reaction that fits the experimental data, and I defined the Ja factor which gives a measure of the cyclization yield independent of DNA initial concentration. This method seems to confirm that minicircles with two gaps cyclize more efficiently that minicircles with two nicks, probably because of the gap flexibility. As a perspective, the conclusions of this thesis could be used for the design of minicircle constructs whose shape would be sensitive enough to sequence mutation in order to be detected by electron microscopy. Such shapes could be then compared, thanks to the shape-distance tool defined herein, to shapes computed with known or putative DNA models.

EPFL2008

Identification and characterisation of small-molecule inhibitors targeting STING

Simone Margret Haag

EPFL2019