Ubiquitin Ligases as molecular targets and novel cancer markers

The aim of our research is to investigate how SCF ubiquitin ligases controls fundamental biological pathways and translate these basic findings with the study of human cancer.

SCF ligases targets specific protein substrates for degradation and this proposal investigates the molecular function and regulatory characteristics of three ubiquitin ligases – SCFFBW7 SCFFBXO28 and SCFFBXL12.Briefly, we will i) investigate pathways associated with replication stress (RS)-induced modulation of oncogenic substrates targeted by FBW7 to define new cancer targets and predictive markers (aim1), ii) identify novel inhibitors that exploit a previously uncharacterized vulnerability of cancer cells – the dependence on functional FBXL12-FANCD2 signaling in response to RS (aim2), iii) explore the dual function of FBXO28-mediated degradation of PIX for regulation of cell motility and repair of heterochromatic DNA breaks.

We have established an international research consortium to molecularly and functionally characterize these enzymes including innovative high-throughput image-based functional screens, omics analysis, animal models and developed the biochemistry tools necessary for the full implementation of the project aims.

The reserch covered within this proposal will provide detailed mechanistic insights into the function of FBW7, FBXL12 and FBXO28 during the oncogenic process that will aid in the discovery of new predictive response markers and key pathways for therapeutic intervention.