Dissecting SUMO Activating Enzyme Pathways to Inform Therapy

One cell becomes two by dividing its DNA, in packets of chromosomes, into two daughter cells. This process is supported by a tiny protein that is added to other proteins to help the packets divide correctly. Correct DNA division is particularly important in some cancers that are driven by a particular genetic change, called Myc amplification. New drugs that stop the small protein from being added appear to be useful in killing cancers that have this genetic change.
We have recently discovered that the target of those drugs behaves in surprising ways. Instead of having a single role as previously thought, we find it has at least two different functions; one of these is in the poorly understood process of helping DNA remain undamaged as it is divided into the daughter cells.
Our aims in this project are to investigate how the drug target behaves in these different ways, to find out which one of them is most important in supporting cancer cell survival, and to discover how it works to prevent DNA damage. This work has implications for how the new drugs are used to help cancer patients.

Drugs targeting the SUMO E1 enzyme (SAE1/2) have emerged as potential chemotherapeutics. However, our understanding of the regulation and behaviour of the E1 is poor. Our preliminary data reveals this enzyme is capable of directing different cellular outcomes and is highly regulated. In the current project, we aim to discover how its regulation directs different outcomes, which aspect is most important to the survival of C-MYC-driven cell growth, and how its activity relates to the maintenance of chromosome integrity. This work has implications for our understanding of how best to use novel E1 inhibitors.