CIISB Research Highlights Archive

  • Angewandte Chemie Int. Ed. 2024

    Angewandte Chemie Int. Ed. 2024

    A tetrastranded DNA structure, KNa-quadruplex (KNaQ), is described. KNaQ forms from repetitive DNA sequences that are abundant in (parasitic) worms but extremely rare in humans or livestock. This opens a possibility of exploiting the fold as a plausible antiparasitic drug target. The structure's unique properties distinguish it from all other known DNA quadruplexes and can be used to design novel recognition DNA elements/sensors.

    Lukáš Trantírek and Martina Zivkovič Research Groups


    DNA quadruplex structures provide an additional layer of regulatory control in genome maintenance and gene expression and are widely used in nanotechnology. We report the discovery of an unprecedented tetrastranded structure formed from a native G-rich DNA sequence originating from the telomeric region of Caenorhabditis elegans. The structure is defined by multiple properties that distinguish it from all other known DNA quadruplexes. Most notably, the formation of a stable so-called KNa-quadruplex (KNaQ) requires concurrent coordination of K+ and Na+ ions at two distinct binding sites. This structure provides novel insight into G-rich DNA folding under ionic conditions relevant to eukaryotic cell physiology and the structural evolution of telomeric DNA. It highlights the differences between the structural organization of human and nematode telomeric DNA, which should be considered when using C. elegans as a model in telomere biology, particularly in drug screening applications. Additionally, the absence/presence of KNaQ motifs in the host/parasite introduces an intriguing possibility of exploiting the KNaQ fold as a plausible antiparasitic drug target. The structure's unique shape and ion dependency and the possibility of controlling its folding by using low-molecular-weight ligands can be used for the design or discovery of novel recognition DNA elements and sensors.

    Gajarsky, M. et al. DNA Quadruplex Structure with a Unique Cation Dependency,

    Angew. Chem. Int. Ed. 2024, e202318261.

  • Nature Communications 2024

    Nature Communications 2024

    Slice through a tomogram of a stage-III ΔspoIVB B. subtilis sporangium, used for the segmentation (ii) of various forespore and mother cell ultrastructures. Panel ii shows the corresponding segmentation.

    Christine Moriscot and Cecile Morlot Research Groups


    Bacterial spores owe their incredible resistance capacities to molecular structures that protect the cell content from external aggressions. Among the determinants of resistance are the quaternary structure of the chromosome and an extracellular shell made of proteinaceous layers (the coat), the assembly of which remains poorly understood. Here, in situ cryo-electron tomography on lamellae generated by cryo-focused ion beam micromachining provides insights into the ultrastructural organization of Bacillus subtilissporangia. The reconstructed tomograms reveal that early during sporulation, the chromosome in the forespore adopts a toroidal structure harboring 5.5-nm thick fibers. At the same stage, coat proteins at the surface of the forespore form a stack of amorphous or structured layers with distinct electron density, dimensions and organization. By analyzing mutant strains using cryo-electron tomography and transmission electron microscopy on resin sections, we distinguish seven nascent coat regions with different molecular properties, and propose a model for the contribution of coat morphogenetic proteins.

    Bauda, E., Gallet, B., Moravcova, J. et al. Ultrastructure of macromolecular assemblies contributing to bacterial spore resistance revealed by in situ cryo-electron tomography.

    Nat Commun 15, 1376 (2024).

  • Nature 2024

    Nature 2024

    Model for ameloblast-specific autoantibody production in patients with coeliac disease.

    Jakub Abramson Research Group


    Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation—amelogenesis. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta. Defects in enamel formation are also found in patients with autoimmune polyglandular syndroze type-1 (APS-1), caused by AIRE deficiency, and in patients diagnosed with coeliac disease. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.

    Gruper, Y., Wolff, A.S.B., Glanz, L. et al. Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease.

    Nature 624, 653–662 (2023).

  • Nature Communications 2023 - 4

    Nature Communications 2023 - 4

    Close-up view of FMA-binding pocket with residues creating the active site in stick representation. Key hydrogen bonds are shown as dashed yellow lines.

    Martin Marek Research Group


    NanoLuc, a superior β-barrel fold luciferase, was engineered 10 years ago but the nature of its catalysis remains puzzling. Here experimental and computational techniques are combined, revealing that imidazopyrazinone luciferins bind to an intra-barrel catalytic site but also to an allosteric site shaped on the enzyme surface. Structurally, binding to the allosteric site prevents simultaneous binding to the catalytic site, and vice versa, through concerted conformational changes. We demonstrate that restructuration of the allosteric site can boost the luminescent reaction in the remote active site. Mechanistically, an intra-barrel arginine coordinates the imidazopyrazinone component of luciferin, which reacts with O2 via a radical charge-transfer mechanism, and then it also protonates the resulting excited amide product to form a light-emitting neutral species. Concomitantly, an aspartate, supported by two tyrosines, fine-tunes the blue color emitter to secure a high emission intensity. This information is critical to engineering the next-generation of ultrasensitive bioluminescent reporters.

    Nemergut, M., Pluskal, D., Horackova, J. et al. Illuminating the mechanism and allosteric behavior of NanoLuc luciferase.

    Nat Commun 14, 7864 (2023).

  • Angewandte Chemie Int. Ed. 2023

    Angewandte Chemie Int. Ed. 2023

    Ultrahigh binding affinity of bambusuril receptors toward halides is achieved and continuously increases with increasing electron-withdrawing power of groups installed on its benzyl substituents, as measured by 1H and 19F NMR spectroscopy.

    Vladimír Šindelář Research Group


    Inspired by nature, artificial hydrogen bond-based anion receptors have been developed to achieve high anion selectivity; however, their binding affinity is usually low. The potency of these receptors is usually increased by the introduction of aryl substituents, which withdraw electrons from their binding site through the resonance effect. Here, we show that the polarization of the C(sp3)-H binding site of bambusuril receptors, and thus their potency to bind anions, can be modulated by the inductive effect. The presence of electron-withdrawing groups on benzyl substituents of bambusurils significantly increases their binding affinities to halides, resulting in the strongest iodide receptor reported to date with an association constant greater than 1013 M−1 in acetonitrile. A Hammett plot showed that while the bambusuril affinity toward halides linearly increases with the electron-withdrawing power of their substituents, their binding selectivity remains essentially unchanged.

    Tuning CH Hydrogen Bond-Based Receptors toward Picomolar Anion Affinity via the Inductive Effect of Distant Substituents, M. Chvojka, D. Madea, H. Valkenier, V. Šindelář

    Angew. Chem. Int. Ed. 2023, e202318261.

  • Cell Reports 2023-2

    Cell Reports 2023-2

    Double-strand breaks (DSBs) are the most severe type of DNA damage. Long et al. show that hSSB1 is modified and forms a trimeric SOSS1 complex that comes to DSBs in an R-loop-dependent manner. At DSBs, SOSS1 and RNA polymerase II form liquid-like repair compartments. Depletion of the SOSS1 impairs DNA repair.

    Monika Gullerova Research Group


    Double-strand breaks (DSBs) are the most severe type of DNA damage. Previously, we demonstrated that RNA polymerase II (RNAPII) phosphorylated at the tyrosine 1 (Y1P) residue of its C-terminal domain (CTD) generates RNAs at DSBs. However, the regulation of transcription at DSBs remains enigmatic. Here, we show that the damage-activated tyrosine kinase c-Abl phosphorylates hSSB1, enabling its interaction with Y1P RNAPII at DSBs. Furthermore, the trimeric SOSS1 complex, consisting of hSSB1, INTS3, and c9orf80, binds to Y1P RNAPII in response to DNA damage in an R-loop-dependent manner. Specifically, hSSB1, as a part of the trimeric SOSS1 complex, exhibits a strong affinity for R-loops, even in the presence of replication protein A (RPA). Our in vitro and in vivo data reveal that the SOSS1 complex and RNAPII form dynamic liquid- like repair compartments at DSBs. Depletion of the SOSS1 complex impairs DNA repair, underscoring its biological role in the R-loop-dependent DNA damage response.

    Long, QL; Sebesta, M; Sedova, K; Haluza, V; Alagia, A; Liu, ZC; Stefl, R; Gullerova, M: The phosphorylated trimeric SOSS1 complex and RNA polymerase II trigger liquid-liquid phase separation at double-strand breaks.

    Cell Reports 42, 113439,

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