PROJECT SUMMARY

This proposal focuses on FBXO11, a substrate receptor for the SKP1-CUL1 E3 ubiquitin ligase complex, which places the ubiquitin post-translational modification onto its target proteins. This modification affects protein stability, localization, and signal scaffolding with the potential to rewire basic cellular functions. My data show that depletion of FBXO11 in MDS models worsens cytopenias in vivo. This suggests that SCF-FBXO11 ubiquitylation activity is an important mediator of MDS biology. I determined that FBXO11 binds a highly-interconnected network of RNA-binding proteins (RBPs), which includes NPM1, an essential gene responsible for ribosome biogenesis. I will test the hypothesis that FBXO11-mediated ubiquitylation of NPM1 restricts MDS progression by dynamically rewiring its stability and localization, with far-reaching effects on the MDS proteome. I will test the role of NPM1 loss in MDS progression and screen for proteins that, when inhibited, could counter this loss. I will also examine the effects of ubiquitylation on protein synthesis. In primary MDS patient samples, I observed disruption of the FBXO11-controlled ribosome and RBP proteome. I will determine if MDS cells deficient in FBXO11 will be sensitized to an inhibitor of ribosome subunits and protein translation, Omacetaxine, which was recently in clinical trials. It is my aim and my hope to understand how the diseased proteome gets remodeled to discover new targets for catastrophic diseases like MDS.