My laboratory determines and leverages the three-dimensional structures of pre-mRNA splice site assemblies to understand and potentially treat human genetic diseases and hematologic malignancies. We focus on the structural and molecular basis for 3´ splice site recognition by the essential splicing factors U2AF65, U2AF35, and SF1. Our recent structures of U2AF65 bound to a range of splice site signals provide a basis for understanding disease-causing mutations in the splice sites of gene transcripts. Towards a view of the higher order splice site assembly, we have revealed phosphorylation-induced conformational changes in the splicing factor subunit SF1 bound to U2AF65, and demonstrated that the phosphorylated interface is essential in vivo. Now, an immediate goal of my laboratory is to determine roadmaps of the key interactions among higher order 3' splice site complexes, and in future phases of the project, assist the development of therapeutics targeted at the level of pre-mRNA splicing.
Our work is enhanced by collaborations with leading researchers in the field of RNA biology and has been documented by peer-reviewed publications in respected journals (including publications in Molecular Cell and Nature Structural & Molecular Biology, impact factors 12.9 and 12.1). I am co-director of the Structural Biology and Biophysics Facility, which supports X-ray crystallographic and biomolecular interaction equipment at the University of Rochester, including a BIAcore T200 that I obtained via an S10 grant from the NIH.
I take pride in the education and placement of members from my group, including graduate students (for example, Karen Thickman, who was an F32 recipient and is now an Assistant Professor at Carnegie Mellon, and Krystle McLaughlin, who was an SPIRE postdoctoral scholar at UNC-Chapel Hill and is now an Assistant Professor at LeHigh University), undergraduate students (for example, Jason Heath, who completed post baccalaureate training at the NIH), and postdoctoral scholars (for example, Allen Sickmier, who is now a Senior Scientist at Amgen, Inc.).
Please visit our lab website for more information.