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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.
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We identified PHF3 as a new transcription elongation factor that directly binds to Pol II CTD via the SPOC domain and regulates neuronal gene expression and neuronal differentiation.
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.
Lisa Appel
PostDoc +43 1 4277 52866
Room: 5.506
Johannes Benedum
PhD Student +43 1 4277 52807
Room: 5.508
Beatriz Dias Ana
PhD Student +43 1 4277 52807
Room: 5.508
Magdalena Engl
PhD Student +43 1 4277 52807
Room: 5.508
Filip Horvat
PostDoc +43 1 4277 52811
Room: 5.610
Ava Kleinwächter
PhD Student +43 1 4277 52807
Room: 5.508
Luca Lippert
Technician +43 1 4277 24001
Room: 5.610
Carla Simon
PhD Student +43 1 4277 52807
Dea Slade
Group Leader +436648001635212
Room: 5.610
Lena Walch
Technician +43 1 4277 00000
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.
Kaufmann Tanja, Grishkovskaya Irina, Polyansky Anton A, Kostrhon Sebastian, Kukolj Eva, Olek Karin M, Herbert Sebastien, Beltzung Etienne, Mechtler Karl, Peterbauer Thomas, Gotzmann Josef, Zhang Lijuan, Hartl Markus, Zagrovic Bojan, Elsayad Kareem, Djinovic-Carugo Kristina, Slade Dea
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 through 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 Tanja, Herbert Sébastien, Hackl Benjamin, Besold Johanna Maria, Schramek Christopher, Gotzmann Josef, Elsayad Kareem, Slade Dea
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.