Investigating WD repeat protein function in the nucleolar biology and cancer

Ribosome biosynthesis is one of the most multifaceted and energy-demanding processes in biology. It involves over 250 factors that transiently associate with the nascent pre-ribosome in a well-orchestrated manner. Importantly, increased ribosome biogenesis has a critical role in cancer initiation and progression. Owing to the advances in cryo-electron microscopy, this pathway’s detailed mechanism started to be revealed, setting the grounds for new therapeutic interventions. The current project seeks to develop chemical probes for WD repeat proteins, a new drug target class. We are particularly interested in targeting WDR12 and WDR55—key components of a nucleolar complex that affect the large ribosomal subunit’s maturation. In this project, we will combine the latest advances in super-resolution microscopy and cell biology to assess WDR12 and WDR55 protein function and interaction networks in cells. Next, binding of inhibitors to the target proteins will be tested using a variety of techniques to establish compound activity and selectivity. Finally, inhibitors will be used to investigate their biological function in nucleolar regulation and glioblastoma tumorigenesis – the most aggressive type of brain cancer. The development of these inhibitors will reveal insights into the biology of this intricate pathway and may provide clinical-translational opportunity for glioblastoma treatment.

Faculty Supervisor:

Dalia Barsyte-Lovejoy

Student:

Raquel Arminda Martinez Machado

Partner:

Structural Genomics Consortium

Discipline:

Pharmacy / Pharmacology

Sector:

Professional, scientific and technical services

University:

University of Toronto