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Jonathan P. Staley

Professor
jstaley@uchicago.edu
Research Summary
Our goal is to understand the mechanism and regulation of nuclear pre-mRNA splicing, an essential step in eukaryotic gene expression. Pre-mRNA splicing is catalyzed by a massive multimegadalton ribonucleoprotein machine called the spliceosome. Using the model organism S. cerevisiae, we apply a wide array of approaches, ranging from single molecule microscopy, biophysics, and chemical biology to biochemistry and cell biology to genetics and genomics to gain a deep understanding of how the spliceosome catalyzes and regulates pre-mRNA splicing.
Keywords
splicing, RNA, Messenger RNA, RNA Sequence, Spliceosome, Intron, Pre-mRNA, ATPase, RNA dependent ATPase, RNA Helicase, DEAD-box RNA Helicases, Gene Expression Regulation, Baker's Yeast, Brewer's Yeast, Yeast Proteins, Exon, Nuclear Export, snRNA, DEAH-box RNA helicase
Education
  • Haverford College, Haverford, PA, B.A. Chemistry 1987
  • Massachusetts Institute of Technology (Advisor: Peter S. Kim), Boston, MA, Ph.D. Chemistry/Biophysics 1993
  • University of California at San Francisco, San Francisco, CA, Postdoc Biochemistry/Genetics 1999
Biosciences Graduate Program Association
Awards & Honors
  • 2000 - 2001 Young Investigator Award Cancer Research Foundation
  • 2001 - 2006 David & Lucile Packard Fellowship in Science and Engineering Packard Foundation
  • 2006 - 2008 Stephen F. Sener, M.D. - Research Scholar Award American Cancer Society
  • 2014 - Distinguished Investigator Award, Biological Sciences Division The University of Chicago
  • 2016 - Fellow American Association for the Advancement of Science
Publications

  1. Profiling lariat intermediates reveals genetic determinants of early and late co-transcriptional splicing. Mol Cell. 2022 12 15; 82(24):4681-4699.e8. View in: PubMed

  2. Termination of pre-mRNA splicing requires that the ATPase and RNA unwindase Prp43p acts on the catalytic snRNA U6. Genes Dev. 2019 11 01; 33(21-22):1555-1574. View in: PubMed

  3. Structure of the DEAH/RHA ATPase Prp43p bound to RNA implicates a pair of hairpins and motif Va in translocation along RNA. RNA. 2017 07; 23(7):1110-1124. View in: PubMed

  4. Specific Recognition of a Single-Stranded RNA Sequence by a Synthetic Antibody Fragment. J Mol Biol. 2016 10 09; 428(20):4100-4114. View in: PubMed

  5. The Evolutionarily-conserved Polyadenosine RNA Binding Protein, Nab2, Cooperates with Splicing Machinery to Regulate the Fate of pre-mRNA. Mol Cell Biol. 2016 11; 36(21):2697-2714. View in: PubMed

  6. Reverse transcriptases lend a hand in splicing catalysis. Nat Struct Mol Biol. 2016 06 07; 23(6):507-9. View in: PubMed

  7. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs. Oncotarget. 2016 May 03; 7(18):26496-515. View in: PubMed

  8. Spliceosomal DEAH-Box ATPases Remodel Pre-mRNA to Activate Alternative Splice Sites. Cell. 2016 Feb 25; 164(5):985-98. View in: PubMed

  9. Sequencing of lariat termini in S. cerevisiae reveals 5' splice sites, branch points, and novel splicing events. RNA. 2016 Feb; 22(2):237-53. View in: PubMed

  10. Knocking Down Snrnp200 Initiates Demorphogenesis of Rod Photoreceptors in Zebrafish. J Ophthalmol. 2015; 2015:816329. View in: PubMed

  11. Evidence for a group II intron-like catalytic triplex in the spliceosome. Nat Struct Mol Biol. 2014 May; 21(5):464-471. View in: PubMed

  12. Synthesis and incorporation of the phosphoramidite derivative of 2'-O-photocaged 3'-s-thioguanosine into oligoribonucleotides: substrate for probing the mechanism of RNA catalysis. J Org Chem. 2014 Apr 18; 79(8):3647-52. View in: PubMed

  13. The DExD/H-box ATPase Prp2p destabilizes and proofreads the catalytic RNA core of the spliceosome. RNA. 2014 Mar; 20(3):282-94. View in: PubMed

  14. RNA catalyses nuclear pre-mRNA splicing. Nature. 2013 Nov 14; 503(7475):229-34. View in: PubMed

  15. Splicing fidelity: DEAD/H-box ATPases as molecular clocks. RNA Biol. 2013 Jul; 10(7):1073-9. View in: PubMed

  16. A conformational switch in PRP8 mediates metal ion coordination that promotes pre-mRNA exon ligation. Nat Struct Mol Biol. 2013 Jun; 20(6):728-34. View in: PubMed

  17. Intronic sequence elements impede exon ligation and trigger a discard pathway that yields functional telomerase RNA in fission yeast. Genes Dev. 2013 Mar 15; 27(6):627-38. View in: PubMed

  18. Spliceosome activation: U4 is the path, stem I is the goal, and Prp8 is the keeper. Let's cheer for the ATPase Brr2! Genes Dev. 2012 Nov 15; 26(22):2461-7. View in: PubMed

  19. Staying on message: ensuring fidelity in pre-mRNA splicing. Trends Biochem Sci. 2012 Jul; 37(7):263-73. View in: PubMed

  20. Meiosis-induced alterations in transcript architecture and noncoding RNA expression in S. cerevisiae. RNA. 2012 Jun; 18(6):1142-53. View in: PubMed

  21. The DEAH box ATPases Prp16 and Prp43 cooperate to proofread 5' splice site cleavage during pre-mRNA splicing. Mol Cell. 2010 Aug 13; 39(3):385-95. View in: PubMed

  22. Spliceosome discards intermediates via the DEAH box ATPase Prp43p. Proc Natl Acad Sci U S A. 2010 Jun 01; 107(22):10020-5. View in: PubMed

  23. Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs. Am J Hum Genet. 2009 Nov; 85(5):617-27. View in: PubMed

  24. Evidence that U2/U6 helix I promotes both catalytic steps of pre-mRNA splicing and rearranges in between these steps. RNA. 2009 Jul; 15(7):1386-97. View in: PubMed

  25. Assembly of ribosomes and spliceosomes: complex ribonucleoprotein machines. Curr Opin Cell Biol. 2009 Feb; 21(1):109-18. View in: PubMed

  26. Long-distance splicing. Proc Natl Acad Sci U S A. 2008 May 13; 105(19):6793-4. View in: PubMed

  27. A role for ubiquitin in the spliceosome assembly pathway. Nat Struct Mol Biol. 2008 May; 15(5):444-51. View in: PubMed

  28. U2 toggles iteratively between the stem IIa and stem IIc conformations to promote pre-mRNA splicing. Genes Dev. 2007 Apr 01; 21(7):821-34. View in: PubMed

  29. DEAD on. Nat Struct Mol Biol. 2006 Nov; 13(11):954-5. View in: PubMed

  30. The EF-G-like GTPase Snu114p regulates spliceosome dynamics mediated by Brr2p, a DExD/H box ATPase. Mol Cell. 2006 Aug 04; 23(3):389-99. View in: PubMed

  31. Exon ligation is proofread by the DExD/H-box ATPase Prp22p. Nat Struct Mol Biol. 2006 Jun; 13(6):482-90. View in: PubMed

  32. The splicing factor Prp43p, a DEAH box ATPase, functions in ribosome biogenesis. Mol Cell Biol. 2006 Jan; 26(2):513-22. View in: PubMed

  33. Multiple functions for the invariant AGC triad of U6 snRNA. RNA. 2004 Jun; 10(6):921-8. View in: PubMed

  34. Hanging on to the branch. Nat Struct Biol. 2002 Jan; 9(1):5-7. View in: PubMed

  35. Specific alterations of U1-C protein or U1 small nuclear RNA can eliminate the requirement of Prp28p, an essential DEAD box splicing factor. Mol Cell. 2001 Jan; 7(1):227-32. View in: PubMed

  36. Neoadjuvant androgen deprivation prior to transperineal prostate brachytherapy: smaller volumes, less morbidity. Cancer J Sci Am. 1999 Nov-Dec; 5(6):370-3. View in: PubMed

  37. An RNA switch at the 5' splice site requires ATP and the DEAD box protein Prp28p. Mol Cell. 1999 Jan; 3(1):55-64. View in: PubMed

  38. Mechanical devices of the spliceosome: motors, clocks, springs, and things. Cell. 1998 Feb 06; 92(3):315-26. View in: PubMed

  39. Formation of a native-like subdomain in a partially folded intermediate of bovine pancreatic trypsin inhibitor. Protein Sci. 1994 Oct; 3(10):1822-32. View in: PubMed

  40. Role of a subdomain in the folding of bovine pancreatic trypsin inhibitor. Nature. 1990 Apr 12; 344(6267):685-8. View in: PubMed

  41. Complete folding of bovine pancreatic trypsin inhibitor with only a single disulfide bond. Proc Natl Acad Sci U S A. 1992 Mar 01; 89(5):1519-23. View in: PubMed
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