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OUR PROJECTS

We study large protein complexes that maintain genome stability and investigate how they function in the context of chromatin. These studies include DNA damage repair, replication, transcription and telomere architecture. As E3 ubiquitin ligases are involved in many of these processes, we are also interested in how E3 ligases recognise their substrates and study small molecule compounds that divert ligase function.

Ubiquitin Biology and Molecular Glues

Protein degradation rapidly inactivates protein function and is used in many biological contexts to trigger irreversible transitions. The major protein degradation pathway, the ubiquitin proteasome system (UPS), includes hundreds of E3 ubiquitin ligases that attach ubiquitin to thousands of substrates, targeting them for proteolytic cleavage by the 26S proteasome. We are interested in how E3 ubiquitin ligases recognize their substrates (Scrima et al., Cell, 2008), and how small molecule compounds such as thalidomide (also known as Contergan or Softenon) divert ligase function to induce degradation of disease-related proteins (Fischer et al., Nature, 2014; Petzold et al., Nature, 2016; Sievers et al., Science, 2018; Slabicki et al., Nature 2020; Kozicka et al., Nat. Chem. Biol. 2024).

 

The Thomä Lab is particularly interested in the degradation of transcription factors, such as the nuclear hormone receptors (NHRs), which are crucial for gene regulation through ligand binding (Tsai et al., Mol. Cell 2023). Medicines targeting NHRs, used in clinical settings for conditions like inflammation and cancers, exploit their druggable nature. We aim to find endogenous and drug-induced mechanisms of transcription factor degradation and investigate how small molecule molecular glues rewire the interactome of proteins. Our approach combines biophysical, biochemical, and structural biology methods, including mass spectroscopy, mass photometry, next-gen sequencing, genetic screens and cryo-EM, to illuminate the intricacies of targeted protein degradation, and to study the rewiring of protein-protein interactions through small molecules (molecular glues).

Transcription Factors in Chromatin Biology

The chromatinized genome regulates transcription by posing physical barriers to the activity of RNA Polymerase II and the binding of transcription factors (TFs). Access to gene promoters is attained via a complex interplay between TFs, transcriptional co-regulators (both activators and repressors) which recognize and alter histone modifications, and chromatin remodelers. The Thomä lab utilizes a combination of structural techniques, biochemistry, and functional assays to dissect how the position and orientation of specific DNA motifs on nucleosomes control TF binding.
We have investigated how TFs such as OCT4-SOX2 (Michael, Grand, Isbel et al., Science, 2020), MYC-MAX, and CLOCK-BMAL1 (Michael et al., Nature, 2023) engage nucleosomes in different positions. We have shown that these TFs trigger DNA distortions by recognizing partial motifs or DNA release and make TF and site-specific histone contacts. Ongoing work aims to understand how TF chromatin occupancy influences upstream and downstream transcription regulation pathways. As a next logical step, the lab will focus on how the complexes between nucleosomes and transcription are decoded by downstream cofactors and the transcriptional machinery.

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