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Interactions define the dynamics of life. Electrostatic interactions provide a transient and tunable response, whereas hydrophobic interactions confer stability. Post-translational protein modifications (PTMs) such as phosphorylation, acetylation and poly(ADP-ribosyl)ation provide a regulatory switch by interfering with these interactions. Our aim is to understand how protein interactions and PTMs fine tune the dynamics of different cellular processes, in particular DNA damage response, DNA replication and transcription. In DNA damage response, PTMs modulate chromatin structure and promote the recruitment of signalling and repair proteins. Within replication factories, PTMs ensure temporal and spatial coordination of replication. During transcription, dynamic phosphorylation of the C-terminal domain of RNA polymerase II and elongation machinery governs the timely recruitment of transcription and RNA processing factors and efficient progression of the transcription cycle. By studying the function and regulation of DNA repair, replication and transcription factors, we aim to understand how their deficiency or misregulation contributes to neurological disorders and cancer.
We apply an integrative approach to address our research questions, including biochemistry, molecular cell biology or stem cell biology. To study protein interactions we use mass spectrometry and in vitro binding assays (isothermal titration calorimetry, fluorescence anisotropy). To probe protein function, we perform CRISPR/Cas9 genome editing in mammalian cells. We use immunofluorescence microscopy and live cell imaging to monitor protein (co)localization and recruitment to laser-induced DNA damage sites. We combine a vast array of functional genomic approaches: RNAseq and TTseq to study transcription, ChIPseq to study genomic occupancy, SLAMseq to study RNA stability. Using an arsenal of different techniques we endeavour to build a complete picture about protein function and regulation.
I obtained my BSc/MSc in Molecular Biology and Pharmacy from the University of Zagreb. I carried out my PhD thesis on DNA repair in the radiation-resistant bacterium Deinococcus radiodurans with Miroslav Radman at the University Pierre et Marie Curie in Paris. As a post-doc I joined Ivan Ahel at the Paterson Institute in Manchester to work on PARG. I started my group at Max Perutz Labs in 2012.
SPOC domains of PHF3, DIDO, RBM15 and SPEN (SHARP) display different affinities and specificities for Pol II CTD phosphomarks. PHF3 and DIDO SPOC specifically recognize tandem pS2, whereas SPEN and RBM15 SPOC preferentially bind pS5. PHF3 and DIDO SPOC primarily mediate interactions with Pol II and the transcription elongation machinery, while RBM15 and SPEN SPOC bind writers and readers of m6A.
PHF3 and DIDO3 paralogues co-regulate transcription by bridging the Pol II elongation machinery with chromatin and RNA processing factors and tethering Pol II in a phase-separated microenvironment. In the absence of PHF3, the DIDO long isoform DIDO3, which contains the SPOC domain, is upregulated to compensate for PHF3 loss as an example of paralogue buffering through isoform switching.
We identified a non-canonical PIP-box in the disordered regulatory region of poly(ADP-ribose) glycohydrolase (PARG) as the PCNA binding motif and showed based on X-ray structure analysis that the PARG PIP-box interacts with PCNA via both hydrophobic and electrostatic interactions. PARG PIP-box is critical for PARG recruitment to DNA damage sites.
PHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC.
Appel, Lisa-Marie; Franke, Vedran; Bruno, Melania; Grishkovskaya, Irina; Kasiliauskaite, Aiste; Kaufmann, Tanja; Schoeberl, Ursula E; Puchinger, Martin G; Kostrhon, Sebastian; Ebenwaldner, Carmen; Sebesta, Marek; Beltzung, Etienne; Mechtler, Karl; Lin, Gen; Vlasova, Anna; Leeb, Martin; Pavri, Rushad; Stark, Alexander; Akalin, Altuna; Stefl, Richard; Bernecky, Carrie; Djinovic-Carugo, Kristina; Slade, Dea
The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators.
Appel, Lisa-Marie; Franke, Vedran; Benedum, Johannes; Grishkovskaya, Irina; Strobl, Xué; Polyansky, Anton; Ammann, Gregor; Platzer, Sebastian; Neudolt, Andrea; Wunder, Anna; Walch, Lena; Kaiser, Stefanie; Zagrovic, Bojan; Djinovic-Carugo, Kristina; Akalin, Altuna; Slade, Dea
The SPOC proteins DIDO3 and PHF3 co-regulate gene expression and neuronal differentiation.
Benedum, Johannes; Franke, Vedran; Appel, Lisa-Marie; Walch, Lena; Bruno, Melania; Schneeweiss, Rebecca; Gruber, Juliane; Oberndorfer, Helena; Frank, Emma; Strobl, Xué; Polyansky, Anton; Zagrovic, Bojan; Akalin, Altuna; Slade, Dea
SPOC domain proteins in health and disease.
Appel, Lisa-Marie; Benedum, Johannes; Engl, Magdalena; Platzer, Sebastian; Schleiffer, Alexander; Strobl, Xué; Slade, Dea
A novel non-canonical PIP-box mediates PARG interaction with PCNA
Tanja Kaufmann, Irina Grishkovskaya, Anton A. Polyansky, Sebastian Kostrhon, Eva Kukolj, Karin M. Olek, Sebastien Herbert, Etienne Beltzung, Karl Mechtler, Thomas Peterbauer, Josef Gotzmann, Lijuan Zhang, Markus Hartl, Bojan Zagrovic, Kareem Elsayad, Kristina Djinovic-Carugo, Dea Slade
PARP inhibition causes premature loss of cohesion in cancer cells.
Kukolj, Eva; Kaufmann, Tanja; Dick, Amalie E; Zeillinger, Robert; Gerlich, Daniel W; Slade, Dea
PARP and PARG inhibitors in cancer treatment.
Slade, Dea
SIRT2 regulates nuclear envelope reassembly via ANKLE2 deacetylation.
Kaufmann, Tanja; Kukolj, Eva; Brachner, Andreas; Beltzung, Etienne; Bruno, Melania; Kostrhon, Sebastian; Opravil, Susanne; Hudecz, Otto; Mechtler, Karl; Warren, Graham; Slade, Dea
Direct measurement of protein-protein interactions by FLIM-FRET at UV laser-induced DNA damage sites in living cells.
Kaufmann, T; Herbert, S; Hackl, B; Besold, J M; Schramek, C; Gotzmann, J; Elsayad, K; Slade, D
Stand-alone P 31112, Stand-alone P 31546, Stand-alone P 36924
2024-2028: The Group Slade participates in the special Doctoral Program "Genome Instability" reviewed and funded by the Austrian Science Fund FWF.
2016-2019: The Group Slade participated in the special Doctoral Program "Integrative Structural Biology" reviewed and funded by the Austrian Science Fund FWF.
2012-2021: The group Slade was an associated member of the special Doctoral Program "Chromosome Dynamics" reviewed and funded by the Austrian Research Fund FWF.
Voyage of the Starships: giant transposons as crucibles of evolution
Parthenogenesis, cryptobiosis, and the survival in extreme environmental conditions
Evading ageing: Mitochondrial and proteostatic adaptations in oocytes
Genomes in Rhodnius prolixus symbiotic system
Stem cells, immune evasion and metastasis in colorectal cancer
Ubiquitin & Friends Symposium 2024
The Ubiquitin & Friends Symposium is an annual international meeting taking place in the beautiful capital of Austria, aiming to bring together scholars from various fields studying ubiquitin/Ubl biology and protein degradation in a personal, family-like atmosphere, as suggested by the name.
The evolution and development of mollusc shells
Unraveling the Complexity of Crossover Regulation in C. elegans
Dynamics of 3D Genome Structure and Function
How superworms can help to solve our plastic waste crisis
Title to be announced
New players in an old pathway: biology of methanogens of the TACK superphylum
Shaping morphogen gradients: from molecules to tissues and back
Title to be announced
Studying stressed cells by in situ structural biology
Exploring Microbial Resilience: Unravelling Escherichia coliand#x27;s Stress Response at the Level of Protein Synthesis
Arbuscular mycorrhiza development and function
Deep homology and deep diversity: Evolving genetic toolkits for making and sensing light
The evolution of cell type identity and tissue microecology at the fetal-maternal interface
The unanticipated roles of PICIs and phages in bacterial evolution
Chemical targeting of subcellular protein localization
Origin and diversification of gut-derived organs in chordates
Job's Dilemma for the Genome: Why Bad Things Happen to Good Chromosomes
Connections between carbon and nitrogen cycling in the ocean
Understanding how the DNA-loop-extruding protein complex Condensin folds a chromatinized genome into mitotic chromosomes
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
From Roads to Rivers? Occurrence and environmental fate of tire and road wear particles and of tire-related chemicals
FENS 2024 Satellite event: Home cage behavior monitoring at the interface of animal welfare and neuroscience
Striking physiology and cell biology of (marine) environmental microorganisms
Mechanisms controlling maintenance of cohesin dependent loops
Title to be announced