Progress Update: Defining the role of PTM on FSHD protein DUX4

Posted by Friends of FSH Research on Dec 27, 2018

Update by Jocelyn O Eidahl PhD

In our second year of funding, we have continued our research to understand the significance of post-translational modifications on DUX4 protein function and toxicity. After a protein is made it can be decorated with certain chemical modifications which are displayed on the protein surface. We refer to these modifications as post-translational modifications or PTMs.

PTMs can alter the protein’s ability to move within a cell, interact with other proteins or DNA, or increase the lifetime of that particular protein, among several other roles. Importantly, PTMs can have a profound role in disease and are being pursued as targets in therapies for a wide-variety of diseases including cancer, autoimmune diseases, cardiovascular disease, kidney disease and age-related disease.

In the first year of funding, our lab’s research determined that the DUX4 protein can be decorated with PTMs. In our second year of funding we have designed studies to determine if adding or removing these modifications could make the protein more or less toxic in cell culture. Specifically, we examined the effects of adding/removing these modifications on toxicity, movement in the cells, lifetime of the protein, induction of FSHD disease biomarkers and promoting DNA damage in human cells. This type of information will be informative when deciding if one or multiple DUX4 PTMs can be a target for designing FSHD therapies.

Additionally, in our second year of funding, we have identified a group of modifying enzymes that could interact with DUX4 to add or remove these PTMs, and began screening the effectiveness of inhibitors targeting some of these enzymes to reduce DUX4 toxicity in cell culture. In the remaining second year of funding, we will continue to screen the effects of adding/removing these modifications on DUX4 protein function and toxicity. Ultimately, we hope this work will help establish a framework for altering the DUX4 protein for FSHD therapeutics.

See grant Defining the role of post-translational modification on FSHD protein DUX4