J. Scott Butler
| Title | Associate Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Microbiology and Immunology |
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| Address | University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 672
Rochester NY 14642
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| Title | Associate Professor |
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| Institution | University of Rochester Medical Center |
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| Department | Cancer Center |
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| Title | Associate Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Biochemistry and Biophysics |
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| 1980 |
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| 1983 | NIH Predoctoral Traineeship in Biochemistry | | 1983 |
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| 1986 | NIH - CNRS Postdoctoral Fellowship | | 1983 |
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| NIH - INSERM Postdoctoral Fellowship - Declined |
One goal of the work in the laboratory is a clear understanding of the mechanisms that ensure the proper expression of messenger RNAs in eukaryotes. The research focuses on a nuclear mRNA surveillance pathway in eukaryotes that destroys aberrant RNAs before they exit the nucleus. Central to this pathway is a conserved complex of proteins called the exosome that degrades RNA molecules that fail to undergo post-transcriptional processing reactions such as polyadenylation and splicing. A major unanswered question addressed by the research is what components of the nuclear exosome and the associated TRAMP complex are required for the processing and degradation of RNAs in the nucleus. This RNA surveillance system guards against the formation of defective RNA-protein complexes that have toxic effects on cell growth and proliferation. Previous studies identified Rrp6p, a nuclear exoribonuclease component of the exosome and showed that it plays a critical role in degrading aberrant RNAs in the nucleus. More recent evidence indicates that a second complex called TRAMP plays a key role in activating RNA substrates for degradation by the nuclear exosome. Experiments underway in the lab aim to (i) identify the components of the TRAMP complex required for enhancement of Rrp6p activity, (ii) elucidate the role that TRAMP and Rrp6p play in a general and a specific pathway for mRNA degradation.
A second project focuses the public health challenge caused by the resurgence of tuberculosis and the spread of antibiotic resistant strains of the causative agent, Mycobacterium tuberculosis. Tuberculosis kills nearly 2 million people each year and estimates put the worldwide population of infected individuals at nearly 2 billion. A majority of these people (90%) carries latent, asymptomatic infections that reactivate causing disease and spread of M. tuberculosis to uninfected individuals. The latent phase and the slow growth rate of M. tuberculosis limit the effectiveness of existing antibiotics. One approach to treatment of tuberculosis would be to design drugs that inhibit the establishment of the latent phase or reactivate growth under conditions allowing aggressive treatment of the infection. Uncharacterized toxin-antitoxin systems in M. tuberculosis may play a role in the establishment and maintenance of the latent phase of infection. Work in the laboratory is designed to (i) test the hypothesis that activation of these systems induces a static metabolic state in cells, (ii) identify the molecular targets of the toxins and (iii) determine the impact of the loss of Pin-toxin function on M. tuberculosis survival during hypoxia-induced latency. These studies will lay the groundwork for a thorough analysis of the molecular biology of these toxin-antitoxin systems with the goal of designing therapeutic approaches to the treatment of latent M. tuberculosis infections.
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Alam A, Miller KA, Chaand M, Butler JS, Dziejman M. Identification of Vibrio cholerae type III secretion system effector proteins. Infect Immun. 2011 Apr; 79(4):1728-40.
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Butler JS, Mitchell P. Rrp6, rrp47 and cofactors of the nuclear exosome. Adv Exp Med Biol. 2011; 702:91-104.
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Butler JS, Mitchell P. Rrp6, Rrp47 and cofactors of the nuclear exosome. Adv Exp Med Biol. 2010; 702:91-104.
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Callahan KP, Butler JS. TRAMP complex enhances RNA degradation by the nuclear exosome component Rrp6. J Biol Chem. 2010 Feb 5; 285(6):3540-7.
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Roth KM, Byam J, Fang F, Butler JS. Regulation of NAB2 mRNA 3'-end formation requires the core exosome and the Trf4p component of the TRAMP complex. RNA. 2009 Jun; 15(6):1045-58.
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Callahan KP, Butler JS. Evidence for core exosome independent function of the nuclear exoribonuclease Rrp6p. Nucleic Acids Res. 2008 Dec; 36(21):6645-55.
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Hoskins J, Butler JS. RNA-based 5-fluorouracil toxicity requires the pseudouridylation activity of Cbf5p. Genetics. 2008 May; 179(1):323-30.
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Callahan KP, Butler JS. Lifting the veil on the transcriptome. Genome Biol. 2008; 9(4):218.
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Fang F, Phillips S, Butler JS. Rat1p and Rai1p function with the nuclear exosome in the processing and degradation of rRNA precursors. RNA. 2005 Oct; 11(10):1571-8.
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Roth KM, Wolf MK, Rossi M, Butler JS. The nuclear exosome contributes to autogenous control of NAB2 mRNA levels. Mol Cell Biol. 2005 Mar; 25(5):1577-85.
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Fang F, Hoskins J, Butler JS. 5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs. Mol Cell Biol. 2004 Dec; 24(24):10766-76.
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Kuai L, Fang F, Butler JS, Sherman F. Polyadenylation of rRNA in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2004 Jun 8; 101(23):8581-6.
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Lum PY, Armour CD, Stepaniants SB, Cavet G, Wolf MK, Butler JS, Hinshaw JC, Garnier P, Prestwich GD, Leonardson A, Garrett-Engele P, Rush CM, Bard M, Schimmack G, Phillips JW, Roberts CJ, Shoemaker DD. Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell. 2004 Jan 9; 116(1):121-37.
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Phillips S, Butler JS. Contribution of domain structure to the RNA 3' end processing and degradation functions of the nuclear exosome subunit Rrp6p. RNA. 2003 Sep; 9(9):1098-107.
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Das B, Butler JS, Sherman F. Degradation of normal mRNA in the nucleus of Saccharomyces cerevisiae. Mol Cell Biol. 2003 Aug; 23(16):5502-15.
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Butler JS. The yin and yang of the exosome. Trends Cell Biol. 2002 Feb; 12(2):90-6.
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Burkard KT, Butler JS. A nuclear 3'-5' exonuclease involved in mRNA degradation interacts with Poly(A) polymerase and the hnRNA protein Npl3p. Mol Cell Biol. 2000 Jan; 20(2):604-16.
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Briggs MW, Burkard KT, Butler JS. Rrp6p, the yeast homologue of the human PM-Scl 100-kDa autoantigen, is essential for efficient 5.8 S rRNA 3' end formation. J Biol Chem. 1998 May 22; 273(21):13255-63.
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Liang S, Briggs MW, Butler JS. Regulation of tRNA suppressor activity by an intron-encoded polyadenylation signal. RNA. 1997 Jun; 3(6):648-59.
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Proweller A, Butler JS. Ribosome concentration contributes to discrimination against poly(A)- mRNA during translation initiation in Saccharomyces cerevisiae. J Biol Chem. 1997 Feb 28; 272(9):6004-10.
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Briggs MW, Butler JS. RNA polymerase III defects suppress a conditional-lethal poly(A) polymerase mutation in Saccharomyces cerevisiae. Genetics. 1996 Jul; 143(3):1149-61.
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Proweller A, Butler JS. Ribosomal association of poly(A)-binding protein in poly(A)-deficient Saccharomyces cerevisiae. J Biol Chem. 1996 May 3; 271(18):10859-65.
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Guo Z, Russo P, Yun DF, Butler JS, Sherman F. Redundant 3' end-forming signals for the yeast CYC1 mRNA. Proc Natl Acad Sci U S A. 1995 May 9; 92(10):4211-4.
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Proweller A, Butler S. Efficient translation of poly(A)-deficient mRNAs in Saccharomyces cerevisiae. Genes Dev. 1994 Nov 1; 8(21):2629-40.
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Patel D, Butler JS. Conditional defect in mRNA 3' end processing caused by a mutation in the gene for poly(A) polymerase. Mol Cell Biol. 1992 Jul; 12(7):3297-304.
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Sadhale PP, Sapolsky R, Davis RW, Butler JS, Platt T. Polymerase chain reaction mapping of yeast GAL7 mRNA polyadenylation sites demonstrates that 3' end processing in vitro faithfully reproduces the 3' ends observed in vivo. Nucleic Acids Res. 1991 Jul 11; 19(13):3683-8.
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Butler JS, Sadhale PP, Platt T. RNA processing in vitro produces mature 3' ends of a variety of Saccharomyces cerevisiae mRNAs. Mol Cell Biol. 1990 Jun; 10(6):2599-605.
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Butler JS, Platt T. RNA processing generates the mature 3' end of yeast CYC1 messenger RNA in vitro. Science. 1988 Dec 2; 242(4883):1270-4.
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Butler JS, Springer M, Grunberg-Manago M. AUU-to-AUG mutation in the initiator codon of the translation initiation factor IF3 abolishes translational autocontrol of its own gene (infC) in vivo. Proc Natl Acad Sci U S A. 1987 Jun; 84(12):4022-5.
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Butler JS, Springer M, Dondon J, Graffe M, Grunberg-Manago M. Escherichia coli protein synthesis initiation factor IF3 controls its own gene expression at the translational level in vivo. J Mol Biol. 1986 Dec 20; 192(4):767-80.
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Springer M, Graffe M, Butler JS, Grunberg-Manago M. Genetic definition of the translational operator of the threonine-tRNA ligase gene in Escherichia coli. Proc Natl Acad Sci U S A. 1986 Jun; 83(12):4384-8.
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Butler JS, Springer M, Dondon J, Grunberg-Manago M. Posttranscriptional autoregulation of Escherichia coli threonyl tRNA synthetase expression in vivo. J Bacteriol. 1986 Jan; 165(1):198-203.
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Springer M, Plumbridge JA, Butler JS, Graffe M, Dondon J, Mayaux JF, Fayat G, Lestienne P, Blanquet S, Grunberg-Manago M. Autogenous control of Escherichia coli threonyl-tRNA synthetase expression in vivo. J Mol Biol. 1985 Sep 5; 185(1):93-104.
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Butler JS, Clark JM. Eucaryotic initiation factor 4B of wheat germ binds to the translation initiation region of a messenger ribonucleic acid. Biochemistry. 1984 Feb 28; 23(5):809-15.
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