Therapeutic targeting of post-transcriptional RNA processing in human diseases

The RNA copies of DNA genes are heavily edited before they can be used by the cell. Internal sequences are removed by splicing, poly(A) tails added, and the nucleotides themselves are often modified. Small molecule and oligonucleotide drugs that perturb RNA processing are poised to revolutionize medicine.

This project will build upon UW–Madison’s strengths in RNA biology and investments in structural biology to create a multi-disciplinary research program to Drug RNA (DRUGR). The goal of DRUGR is to discover new RNA-based or RNA-targeting therapies for human disease. The project team combines complementary areas of expertise (biochemistry, chemistry, single molecule physics, structural biology) and parallel research tracks to acquire knowledge and meet our goals. As an initial target, the team will focus on identifying small molecule drugs that correct splicing defects due to loss of the LUC7L2 gene in myeloid neoplasms. The goals are to build and benchmark novel DRUGR-STRUCTR and DRUGR-MAP platforms with new discoveries about the biochemistry and structures of LUC7L, LUC7L2, and LUC7L3 proteins. Goldsmith and Hoskins will use massively parallel arrays of RNAs to study binding of the LUC7L proteins to RNAs on the transcriptome scale. By combining these arrays with small molecule drug libraries, compounds will be identified that can rewire cellular RNA processing for therapeutic benefit. Butcher and Grant will use X-ray crystallography and cryo-EM to structurally characterize LUC7 proteins in complex with their RNA binding sites, bound to splicing factors, and in complex with drug candidates. These experiments will provide the foundation for obtaining federal funding for a tiered research enterprise at UW–Madison called The Center for Ribonucleoprotein Research and Drug Discovery.

PRINCIPAL INVESTIGATOR

Aaron Hoskins, associate professor of biochemistry and chemistry, Wasson Professor in Biochemistry of Higher Animals

CO-PRINCIPAL INVESTIGATORS

Samuel Butcher, professor of biochemistry, Steenbock Professor of Biomolecular Structure

Randall Goldsmith, professor of chemistry

Tim Grant, assistant professor of biochemistry and affiliate with the Morgridge Institute for Research