microRNA BIOGENESIS

The major aim of laboratory is to determine mechanisms of non-canonical gene expression regulation and to use structural information to facilitate development of novel small molecule inhibitors. Our group has determined crystal structures of Lin28 with three microRNAs. Lin28 is a reprogramming factor and an oncogene. High-resolution crystal structures of Lin28/microRNA complexes provide new avenues for cancer drug discovery projects. We aim to determine X-ray and EM structures of other complexes from this pathway. Our work in this area is funded by the National Cancer Institute. In collaboration with Prof. Walker’s laboratory we also determined crystal structures of the O-GlcNAc Transferase (OGT) and its complex with a peptide substrate. This structural work was complemented by a molecular dynamics simulation performed on a specialized computing cluster developed in my laboratory. Future collaborative work on OGT will focus on the development of small inhibitors and is funded by NIH/NIGMS. 

 

Selected publications and supporting data:

MicroRNA Biogenesis:

  • E Ransey, A Björkbom, VS Lelyveld, P Biecek, L Pantano, JW Szostak, P Sliz (2017). Comparative analysis of LIN28-RNA binding sites identified at single nucleotide resolution. RNA Biology. Preprint.

  • L Wang, Q Yang, A Jaimes, T Wang, H Strobelt, J Chen, P Sliz. (2017) MightyScreen: An Open-Source Visualization Application for Screening Data Analysis. SLAS DISCOVERY: Advancing Life Sciences R&D, 2472555217731983. Journal Access

  • L Wang, Y Nam, AK Lee, C Yu, K Roth, C Chen, EM Ransey, P Sliz. (2017) LIN28 zinc knuckle domain is required and sufficient to induce let-7 oligouridylation. Cell Reports 18 (11), 2664-2675. Open Access

  • VS Lelyveld, A Björkbom, EM Ransey, P Sliz, JW Szostak. (2015Pinpointing RNA-protein crosslinks with site-specific stable isotope labeled oligonucleotides. J. Am. Chem. Soc 137 (49), 15378-15381. Open Access 

  • P Du, L Wang, P Sliz, RI Gregory (2015). A Biogenesis Step Upstream of Microprocessor Controls miR-17∼92 Expression. Cell 162, 885–99.

  • Thornton, J.E., Du, P., Jing, L., Sjekloca, L., Lin, S., Grossi, E., Sliz, P., Zon, L.I., and Gregory, R.I. (2014). Selective microRNA uridylation by Zcchc6 (TUT7) and Zcchc11 (TUT4). Nucleic Acids Res. 42, 11777–11791.

  • Nam Y, Chen C, Gregory RI, Chou J, Sliz P (2011). Molecular Basis for Interaction of let-7 MicroRNAs with Lin28. Cell; 5:1080-91. PDF 
    PDB Files: 3TRZ, 3TS0, 3TS2.
    Diffraction Datasets: Structural Biology Data Grid

  • Piskounova, E., Viswanathan, S.R., Janas, M., LaPierre, R.J., Daley, G.Q., Sliz, P., and Gregory, R.I. (2008). Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28. J. Biol. Chem. 283, 21310–21314.

Other:

  • AW Kulczyk, A Moeller, P Meyer, P Sliz, CC Richardson (2017). Cryo-EM structure of the replisome reveals multiple interactions coordinating DNA synthesis. Proceedings of the National Academy of Sciences 114 (10), E1848-E1856. Open Access

  • E Bailey, Y Cui, A Casey, JM Stoler, X Ai, D Ma, R Handin, P Sliz,  SO Vargas, SY El-Chemaly (2017). Pulmonary Vasculopathy Associated with FIGF Gene Mutation. The American journal of pathology 187 (1), 25-32.

  • Lazarus MB, Nam Y, Jiang J, Sliz P*, Walker S*. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 2011; 469:564-7.
    Data: 1μs Desmond MD Trajectory

  • Jiang J, Lazarus MB, Pasquina L, Sliz P, Walker S. A neutral diphosphate mimic crosslinks the active site of human O-Glcnac transferase. Nature Chemical Biology 2012; 1:72-77. PMC3241908

  • Yuan, Y., Barrett, D., Zhang, Y., Kahne, D., Sliz, P., and Walker, S. (2007). Crystal structure of a peptidoglycan glycosyltransferase suggests a model for processive glycan chain synthesis. Proc. Natl. Acad. Sci. U.S.A.104, 5348–5353.

  • Kim, S., Malinverni, J.C., Sliz, P., Silhavy, T.J., Harrison, S.C., and Kahne, D. (2007). Structure and function of an essential component of the outer membrane protein assembly machine. Science 317, 961–964.

  • Nam, Y., Sliz, P., Song, L., Aster, J.C., and Blacklow, S.C. (2006). Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124, 973–983.

  • Gonen, T., Cheng, Y., Sliz, P., Hiroaki, Y., Fujiyoshi, Y., Harrison, S.C., and Walz, T. (2005). Lipid-protein interactions in double-layered two-dimensional AQP0 crystals. Nature 438, 633–638.

  • Gonen, T., Sliz, P., Kistler, J., Cheng, Y., and Walz, T. (2004). Aquaporin-0 membrane junctions reveal the structure of a closed water pore. Nature429, 193–197.

  • Fotin, A., Cheng, Y., Sliz, P., Grigorieff, N., Harrison, S.C., Kirchhausen, T., and Walz, T. (2004). Molecular model for a complete clathrin lattice from electron cryomicroscopy. Nature 432, 573–579.

  • Sliz, P., Harrison, S.C., and Rosenbaum, G. (2003). How does radiation damage in protein crystals depend on X-ray dose? Structure 11, 13–19.

 

 

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