Grant: Project Grant

The effective structural regulation and utilization of a cell's genetic material is essential to its fitness. Unsurprisingly, it is now clear that epigenetic regulators, proteins that organize and regulate the accessibility of the genetic material, are commonly altered in human diseases, including cancer. Notably, the SWI/SNF chromatin remodeling complexes are among the most commonly mutated protein complexes in human cancers, with ~20% of patients possessing at least one affected subunit. Intriguingly, SWI/SNF complexes contain a high density of bromodomains, conserved protein domains responsible for binding acetylated lysine residues, suggesting that they may have important functions in these complexes. In recent years, bromodomains have become actionable therapeutic targets, with the development of numerous small molecule inhibitors that effectively and specifically block their function. Clinical trials investigating these innovative inhibitors are ongoing in Canada and elsewhere. Unfortunately, fundamental understanding of the functions of the ten bromodomains incorporated in SWI/SNF complex components is still lacking. This project aims to provide this knowledge by employing state-of-the-art tools to identify the cellular targets of SWI/SNF bromodomains, examine how they engage these targets, and determine the functions of these interactions. This will aid in predicting the molecular consequences of specific mutations within SWI/SNF complex components, support the ongoing development of novel bromodomain inhibitors, and further our understanding of the regulatory processes controlling a cell's genomic material.