Cancer

Sidharth Sirdeshmukh

Research Associate, Dewpoint

Sumoylation is a post-translational modification that organizes and coordinates systematic processes within cells. One of these processes that people are interested in is targeted protein degradation. E3 ligases are ultimately responsible for depositing SUMO proteins onto target proteins, and scientists are hoping that the process of identifying sumoylated proteins (target proteins), and then tuning SUMO deposition will enable programmed upregulation and downregulation of these targets to conquer disease. Because sumoylation (and ubiquitinoylation) is reversible, the goal would be to somehow sustain this phenotype. However, it’s probably more nuanced than this- there is likely a threshold within the SUMO-cycle that needs to be met in order to activate proteolytic degradation of target proteins. This review says that SUMO encourages LLPS among proteins known to be sumoylated. So, why not run a dose-response curve that induces ‘spot formation’ with these target proteins, in disease-relevant cells. You will likely observe the ‘dose window’ where spot formation begins, intensifies, and then disappears altogether. Then, running closer doses within this window and fixing cells on timepoints would help to understand the ‘time+concentration’ combinations that would trigger degradation of target proteins. Bigger, conceptual questions are 1) Do we want sustained or sporadic spot formation? 2) Does sustained spot formation even mean that degradation of target proteins will take place? 3) Is it possible that LLPS is occluding the observation/ access of SUMOd proteins by proteases? 4) Sumo is also an additive process, so is it possible that spot area/ intensity, rather than formation, will lead us in the right direction? 5) Are there peripheral proteins that may modulate SUMO-LLPS dynamics that would be worth monitoring in relation to target proteins?