Development of Deubiquitinase Targeted Chimeras (DUBTACs) to Increase Protein Levels.

Ubiquitin is a regulatory protein whose addition to substrates can signal for a protein to be degraded and is also involved in other processes such as trafficking.

PROTACs (proteolysis targeting chimeras) have recently been developed, which act to recruit the cellular machinery to attach ubiquitin to a protein of interest and tag it for degradation by the proteasome.

Our approach is analogous but opposite to this; we aim to develop DUBTACs (deubiquitinase targeting chimeras) to remove ubiquitin from our target protein and prevent degradation, and therefore prolong the duration of cellular activity or potentially turn off ubiquitin dependent signalling in the cell.

This has a broad scope of impact; many disease states are caused by proteins that are degraded too readily and so could be targeted by this approach such as such as Cystic Fibrosis (CFTR protein), Long QT syndrome (KCNQ1) as well as tumour suppressor proteins in Cancer [4,5].