Laboratory Andrea Pichler
Posttranslational modifications are powerful tools to reversibly modulate protein functions. They allow the dynamic control of cellular processes like transcription, intracellular transport, DNA replication & repair, cell cycle progression or meiosis without the need of de novo protein synthesis. Besides phosphorylation, methylation or acetylation, the attachment of ubiquitin and SUMO (small ubiquitin related modifier) are amongst the most frequently used reversible modifications.
SUMO is a small protein that regulates protein functions like protein stability, activity or intracellular localization. The covalent attachment of SUMO to its substrates, called sumoylation, is executed by the hierarchical action of E1, E2 and E3 enzymes. Sumolylation is essential for viability in most organisms and highly induced upon stress conditions to coordinate key functions in stress response like DNA damage repair. Thus, deregulation of this system is implicated in the pathogenesis of diverse diseases including cancer, neurodegeneration or infections. Constitutive high levels of sumoylation correlate with adaptation to anti-cancer treatments and tumor relapse.
Our aim is to disclose the molecular mechanisms of how SUMO conjugation is regulated via E2 and E3 enzymes, how these enzymes get activated upon stress treatments, the complexity of their substrate spectra and their biological functions in stress response.
In our studies, we put strong emphasis on biochemical approaches in combination with general cell biology to gain conceptual novel insights into the complexity of regulatory SUMO enzymes. As proof of principle, our focus is on E2 (Ubc9) regulation via sumoylation and on the ZNF451 family that we identified as a novel class of stress regulated SUMO E3 ligases.
Our research aims to understand how sumoylation enzymes are regulated, select their substrates and contribute to cellular stress response. Obtained insights into the biological functions unveil likely participation in disease onset/prevention and whether these enzymes represent druggable targets for a combinatorial anticancer therapy.
Inhibitors of the single E1 and the E2 enzymes are already in clinical trails. However, specific E3 ligase inhibitors are supposed to be superior as they show higher specificity and are therefore expected to cause less side-effects.