Due to its name, it’s not difficult to think of the ubiquitination pathway as having a role in almost all cellular processes. However, until recently the evidence linking ubiquitin receptors with the regulation of gene expression was limited at best. Now, researchers from the Institute for Research Biomedicine in Barcelona (IRB Barcelona) have revealed an additional role for the protein dDsk2, beyond its protein degradation functions, as an epigenetic regulatory molecule.  

“Although previous data pointed to the possibility of ubiquitin receptors,” stated Ferran Azorín, Ph.D., group leader at IRB Barcelona and senior author on the current study. “Data were scarce and a direct role in gene regulation had not been demonstrated.”

The findings from this study were published recently in Nature Communications through an article entitled “dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes.”

Typically, ubiquitin receptors recognize a protein that is tagged with ubiquitin and remove it from the cell through the proteasomal degradation pathway, which is comprised of roughly 100 proteins whose functions vary widely within the destruction process.    

However, using fruit flies as their genetic model, Dr. Azorín and his colleagues noticed that the ubiquitin receptor protein dDsk2 had a nonproteolytic role in transcription regulation—a dramatic departure from its typical proteolytic duties.

“Ubiquitination related to transcription proteins and to DNA repair had previously been described,” explained Dr. Azorín. “But this is the first time that a protein, dDsk2, which recognizes the ubiquitination of a histone, a protein that forms part of chromatin, has been identified.”

Chromatin is a complex formed when DNA winds itself tightly around histone proteins, which is then packaged into chromosomes. Chromatin was originally viewed as a mechanism to enable the cell to stuff copious amounts of DNA into the nucleus. Yet, over the past decade or more, scientists have shown that the chromatin structure is responsible for gene regulation at least as much as it is for packaging—a discovery that helped launch the burgeoning field of epigenetics.

Additionally, mutations in the protein ubiquilin, the human homolog of dDsks, have been associated with neurodegenerative pathologies such as Alzheimer’s and Huntington’s disease. “The role of these mutations in the onset and development of disease is still unknown,” said Johan Tisserand, Ph.D., postdoctoral research in Dr. Azorín's lab and co-author on the current study. The possibility of a finding a link between epigenetic regulation and ubiquitination and that having a role in neurodegenerative disease is an exciting and novel concept, one that Dr. Tisserand plans on pursuing in greater depth.  

The findings from this current study has excited Dr. Azorín and his team, who are in the process of developing new assays to reveal the underlying pathway involved in the dDsk2 function, using both Drosophila and in vitro human cells.  

“Now that we have discovered this new function, we aim to study whether it affects degradation or transcription, although probably both processes are altered. Our goal is to work towards unraveling these effects,” Dr. Azorín concluded.