Our Research Focus
The Role of RNA-Binding Protein Mutations in Disease
Increased accessibility to whole exome sequencing has helped identify RBP mutations in cancer and neurodevelopmental diseases. The Malaney Lab is specifically focused on mutations in a family of RBPs called hnRNPs (heterogenous nuclear ribonucleoproteins) and their contribution to malignancy and neurodevelopmental disease. The overall goal in the lab is to unravel the mechanistic basis of the pathogenicity of hnRNP mutations to identify therapeutic vulnerabilities
Ribosome Biogenesis and Function
RBPs regulate several critical processes within the cell, thereby playing a crucial role in maintaining cellular homeostasis. Any changes in RBP levels disrupt these critical processes resulting in a pathogenic state.
Consequently, some RBPs have been shown to have dual tumor suppressor and oncogene functions. We therefore refer to these RBPs as Goldilocks genes wherein their levels must be “just right” to ensure cellular health.
Data from our lab shows that one of the critical processes regulated by RBPs is ribosome biogenesis and translation. Ribosome biogenesis, the process of generating the protein synthesizing structure of the cell, is one of the most energy-demanding processes in the cell. This multi-step process involves the production of ribosomal RNA (rRNA) as well as ribosomal proteins to create the functional ribosomal subunits. These subunits are synthesized in the nucleolus and subsequently transferred to the cytoplasm where they assemble into the functioning ribosome. Because of the dramatic impacts of protein synthesis on cellular homeostasis, dysregulation and abnormalities in ribosome biogenesis are implicated in many human diseases and cancers. However, an in-depth understanding of how RBPs interact with rRNA and effect ribosome biogenesis and translation is still lacking. In the Malaney Lab, we use polysome profiling, ribosome profiling, proteomics and molecular biology techniques to understand the role of hnRNPs in ribosome biogenesis and function.