Pichler Group

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) belongs to 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. Sumoylation 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, dysregulation 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.

In our studies, we emphasize on biochemical approaches in combination with general cell biology to gain conceptual novel insights into the complexity of regulatory SUMO enzymes. Our focus is on E2 (Ubc9) regulation via sumoylation its substrate EME1 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. The insights gained into the biological functions provide information about the likely involvement in disease development or prevention and whether these enzymes represent targets for combinatorial cancer therapy.
Inhibitors of the individual E1 and E2 enzymes are already in clinical trials. However, specific E3 ligase inhibitors are thought to be superior because they have higher specificity and are therefore expected to cause fewer side effects.