| dc.description.abstract | WDR5 is a conserved WD40-repeat protein that rose to prominence through its role in epigenetic complexes, including the KMT2 (MLL/SET) enzymes that deposit histone H3 lysine 4 methylation and the non-specific lethal complex that lays down H4 lysine 16 acetylation. But WDR5 has functions outside these complexes, including recruiting MYC to chromatin, controlling expression of genes linked to protein synthesis, enabling rapid gene reactivation upon exit from mitosis, and promoting faithful assembly of the mitotic spindle. Why and how WDR5 participates in so many processes are unclear, as is the extent to which its moonlighting capabilities have been revealed. WDR5 is also a promising pharmacological target in cancer, with most drug discovery efforts directed against an arginine-binding cavity in WDR5 called the WIN site. Despite a clear expectation that WIN site inhibitors will alter the repertoire of WDR5 interaction partners, their impact on the WDR5 interactome remains unknown. Here, I apply proteomic, biochemical, and genomic techniques to examine the effects of WIN site inhibition. Using quantitative proteomics I find that WIN site inhibitor alters the interaction of WDR5 with dozens of proteins, including several linked to phosphatidylinositol 3-kinase (PI3K) signaling. I demonstrate that the master kinase PDPK1 is a high-affinity WIN site binding protein that engages WDR5 to modulate transcription of genes expressed in the G2 phase of the cell cycle. I also find that MYC interacts with PDPK1 in a WDR5-dependent manner, indicating that WDR5 might function in a trimeric complex with MYC and PDPK1. This research expands our understanding of the roles of WDR5, hones definition of what constitutes an avid WIN site binder, and reveals how WIN site inhibition can impact the WDR5 interactome. | |
