Eldorado - Repository of the TU Dortmund
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Mammalian proteome profiling reveals readers and antireaders of strand-symmetric and -asymmetric 5-hydroxymethylcytosine-modifications in DNA
(2026-01-04) Engelhard, Lena; Cakil, Zeyneb Vildan; Zambrano-Mila, Marlon S.; Eppmann, Simone; Gonzalez, Tye; Linser, Rasmus; Janning, Petra; Becker, Sidney; Summerer, Daniel
The cytosine (C) modifications 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) are central regulatory elements of mammalian genomes. Both marks occur in double-stranded DNA in either strand-symmetric or -asymmetric fashion, but it is still poorly understood how this symmetry information is selectively read out by the nuclear proteome as the basis of potential symmetry-dependent regulation. We report enrichment/proteomics studies with promoter probes being strand-symmetrically or asymmetrically modified with C, mC, and hmC, enabling comparison of their reader profiles in the same sequence, tissue, and experimental contexts. We identify a high number of tissue-specific readers for hmC-modified sequences that fall into distinct, probe-specific sub-groups, including members of important transcription factor classes and chromatin regulators. Among them, we discover the master regulators MYC and MAX that play central roles in cell (de)differentiation and cancer progression to read hmC in a sequence-dependent manner. We also find RFX5, a transcription factor involved in primary MHC class II deficiency, to discriminate between hmC symmetries in CpG dyads. Our findings provide further support for the hypothesis that hmC symmetry information can provide distinct regulatory outputs and provide a resource for studying the molecular mechanisms triggered by symmetric and asymmetric hmC modifications in chromatin regulation during development and disease.
Modelling interexceedance times of temporally clustered extreme events
(2025) Mathieu, Christina Henrika; Fried, Roland; Schorning, Kirsten
This dissertation presents a unified framework for modelling interexeedance times of temporally clustered extreme events. Building on two established models, we introduce a generalised model, which combines underlying stationary magnitudes with random, heavy-tailed waiting times. When a sufficiently high threshold is used to define exceedances, the resulting interexceedance times follow a mixture of a Dirac measure at zero and a Mittag-Leffler distribution.
The generalized mixed distribution is characterised by three parameters: the tail index, the extremal index, and a scale parameter. To estimate them from data, we propose two minimum distance estimators (CMmod1 and CMmod2) based on modified Cramér-von Mises distances. Their weak consistency is shown theoretically, and their finite sample performance is assessed through extensive simulations. Results highlight CMmod2's robustness to threshold selection and parameter constellations. The estimators are also evaluated against existing methods in the special cases of the compound Poisson process and the fractional Poisson process. Despite requiring the estimation of an additional parameter, CMmod1 and CMmod2 show competitive accuracy, suggesting that explicit model selection may be avoidable.
A case study on North Atlantic cyclone data illustrates the practical value of the FCPP, revealing spatial differences in clustering behaviour and confirming the real-world applicability of the proposed methodology.
Smarte Tools für servicezentrierte Anwendungen in Wertschöpfungsnetzwerken
(2025-12-17) Eichholz, Jonas; Schrage, Tobias; Große, Nick; Karabulut, Diyar; Jungh, Leon; Tchapga Leumen, Marius Klinsmer; Henke, Michael
Charge-neutral Zn(II) helicates for chiroptical recognition and guest exchange
(2025) Kalarikkal, Malavika G.; Van Craen, David; Clever, Guido
The discipline of anion recognition chemistry is integral to the domain of supramolecular chemistry, with the primary aim of formulating receptors that can selectively bind anions, particularly under competitive conditions. The field has witnessed substantial progress through the innovation of our charge-neutral double-stranded zinc(II) helicates. These helicates are designed to facilitate high-affinity binding of various aliphatic and aromatic dicarboxylates that are both environmentally and biologically significant. Notably, the hydroxyquinoline-based L2Zn2 helicates demonstrate remarkable binding constants that exceed 108 M-1, enabling the size-selective binding of dicarboxylate anions at nanomolar concentrations. This helicate effectively bridges the gap between conventional organic and charged metal-assembled receptors, providing a stable, charge-neutral platform that is resistant to interference from counter anions.
Building on this high-affinity anion recognition, we explored the chiroptical properties of zinc(II) helicates that incorporate stereodynamic quinolinate zinc complex units to form either a meso structure or racemic mixtures of right- and left-handed helicates. Upon the specific recognition of chiral mono- or dicarboxylates, these helicates demonstrate distinct circular dichroism (CD) responses, facilitating precise chirality analysis and determination of enantiomeric excess. Notably, the binding of tartrate results in the enrichment of one of the helicate enantiomers within the racemic population, producing pronounced Cotton effects in the CD spectrum. This receptor-based methodology offers high-throughput screening capabilities with minimal solvent use and waste generation, presenting a practical alternative to chromatographic techniques that depend on chiral stationary phases.
The strong coordinative interaction with the guest is advantageous in most cases, as it provides high binding constants and enables highly sensitive recognition of carboxylates even at nanomolar levels. However, this interaction poses challenges in the release of the guest from the system. The helicate's notable size-selectivity for various guests, which could be a beneficial characteristic for sensing applications, is compromised by the inability to achieve controlled guest release within the coordination framework. In an approach to establish a controlled release mechanism for guests without necessitating alterations to the host framework, which could potentially modify its inherent properties, a stimuli-responsive guest was incorporated into the system. Azobenzene-4,4’-dicarboxylate, which can utilize its light- and temperature-responsive isomerization states, serves as a competing guest within the L2Zn2 receptor. The size difference between its bent cis isomer and its extended trans form permits the selective accommodation of the former within the zinc pocket, thereby facilitating photo- and thermally induced guest exchange cycles in the presence of a secondary, non-photoactive guest. The azobenzene guest's transition between its different geometric states provides a mechanistic pathway for the second guest to bind and release in a controlled manner.
In order to further exploit the selective binding properties, we aimed to design a colorimetric sensor unit for the helicate in the context of guest binding. To achieve this, the host design was modified by integrating a triphenylamine (TPA) unit into the backbone, with the intention of enhancing the photophysical properties of the host. Although the assembly was successfully executed, it did not result in the anticipated improvements. Subsequent investigations involving environmentally relevant perfluorinated guests revealed low-affinity behavior. The incorporation of TPA as a donor moiety in this new receptor design may open up potential applications in donor-acceptor systems and related fields.
Mass spectrometric analysis of small-molecule-induced ubiquitination and deubiquitination
(2025) Führer, Siska; Waldmann, Herbert; Gersch, Malte
The therapeutic targeting of the ubiquitin system is a growing field in chemical biology. Thus, the need to reliably detect small-molecule-induced alterations of protein ubiquitination is emerging. At the same time, there is a lack of methods for the unbiased and broad screening of small molecules for their ability to target the ubiquitin system.
This thesis describes the establishment of a mass-spectrometric method to detect changes in the cellular polyubiquitome upon treatment of mammalian cells with different small molecules.
The assay involves the enrichment of polyubiquitinated proteins from cell lysate using a tandem ubiquitin binding entity, followed by the digestion of the polyubiquitome, and its analysis by LC-MS/MS.
Application to different small molecule treatments showed the enrichment of PROTAC target proteins from cells with inhibited proteasome. The method further demonstrated its versatility in the context of an intact proteasome and deubiquitinase inhibitors by also covering non-degradative ubiquitination.
Finally, applying the method to uncharacterized research compounds showed the versatility and quality of the assay to recognize subtle changes in protein polyubiquitination. Collectively, the enrichment of polyubiquitinated proteins coupled to mass spectrometry provides a valuable addition to the repertoire of proteomics-based methods for the discovery and characterization of small molecules targeting the ubiquitin system.