B.S., Montana State University Ph.D., University of Washington/FHCRC Postdoctorate, Brandeis University

Structural and Functional Analysis of Spliceosomes My lab uses the tools of structural biology and biochemistry to investigate the cellular machinery responsible for editing the information contained in the RNA transcripts of nearly all of human genes. This machinery, called the spliceosome, splices out intron sequences that interrupt gene transcripts and joins exon sequences to make messenger RNAs that correctly encode for proteins. The goal of our research is to understand how the spliceosome is assembled and how it catalyzes the splicing reaction, but this is hampered by how relatively little we know about the spliceosome's architecture. The spliceosome presents special challenges to structure determination. It is assembled from many parts including 5 structural RNAs and on the order of 100 different proteins. Additionally, the spliceosome is a dynamic machine, cycling through many short-lived conformations during the splicing process. Our research group is meeting these challenges by combining structural and biochemical techniques to study the spliceosome. For example, we use electron microscopy to directly image very limited amounts of splicing complexes that we can isolate. We employ image processing procedures that, in combination with labeling studies, we use to develop 3D models of the spliceosome. In parallel, we use a variety of biochemical methods, including mass spectrometry and high throughput screening, to capture and characterize different spliceosome conformations and to study individual complex components. As we continue to further our biochemical and structural understanding of the spliceosome, we will generate increasingly detailed models of this important cellular machine that will finally shed a light on the mechanistic underpinnings of splicing.

Human RNF113A participates of pre-mRNA splicing in vitro. Gatti da Silva GH, Jurica MS, Chagas da Cunha JP, Oliveira CC, Coltri PP. J Cell Biochem. 2018 Dec 2. doi: 10.1002/jcb.28163. [Epub ahead of print] Enantioselective Synthesis of a Cyclopropane Derivative of Spliceostatin A and Evaluation of Bioactivity. Ghosh AK, Reddy GC, Kovela S, Relitti N, Urabe VK, Prichard BE, Jurica MS. Org Lett. 2018 Nov 16;20(22):7293-7297. doi: 10.1021/acs.orglett.8b03228. Epub 2018 Nov 5. Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition. Ghosh AK, Veitschegger AM, Nie S, Relitti N, MacRae AJ, Jurica MS. J Org Chem. 2018 May 4;83(9):5187-5198. doi: 10.1021/acs.joc.8b00593. Epub 2018 Apr 26. Prp8 positioning of U5 snRNA is linked to 5' splice site recognition. MacRae AJ, Mayerle M, Hrabeta-Robinson E, Chalkley RJ, Guthrie C, Burlingame AL, Jurica MS. RNA. 2018 Jun;24(6):769-777. doi: 10.1261/rna.065458.117. Epub 2018 Feb 27. Enantioselective Synthesis of Spliceostatin G and Evaluation of Bioactivity of Spliceostatin G and Its Methyl Ester. Ghosh AK, Reddy GC, MacRae AJ, Jurica MS. Org Lett. 2018 Jan 5;20(1):96-99. doi: 10.1021/acs.orglett.7b03456. Epub 2017 Dec 8. Modulating splicing with small molecular inhibitors of the spliceosome. Effenberger KA, Urabe VK, Jurica MS. Wiley Interdiscip Rev RNA. 2017 Mar;8(2). doi: 10.1002/wrna.1381. Epub 2016 Jul 21. Review. Design, synthesis and in vitro splicing inhibition of desmethyl and carba-derivatives of herboxidiene. Ghosh AK, Lv K, Ma N, Cárdenas EL, Effenberger KA, Jurica MS. Org Biomol Chem. 2016 Jun 21;14(23):5263-71. doi: 10.1039/c6ob00725b. Epub 2016 May 18. Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages. Effenberger KA, Urabe VK, Prichard BE, Ghosh AK, Jurica MS. RNA. 2016 Mar;22(3):350-9. doi: 10.1261/rna.053108.115. Epub 2016 Jan 7.