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James S. Butler, Ph.D.

James S. Butler, Ph.D.

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About Me

Faculty Appointments

Professor Emeritus - Department of Microbiology and Immunology (SMD)

Credentials

Post-doctoral Training & Residency

University of Rochester, Postdoc., Molec. Biol. 1987 - 1989

Institut de Biologie Physico-chimique, Paris 1984 - 1987

Education

PhD | Univ of Illinois-Urbana. Biochemistry. 1984

BS | Univ Wisconsin-Madison. Biochemistry. 1979

Awards

Graduate Alumni Award. 2017

Outstanding Program Director Award. 2013

NIH - CNRS Postdoctoral Fellowship. 1983 - 1986

NIH - INSERM Postdoctoral Fellowship - Declined. 1983

NIH Predoctoral Traineeship in Biochemistry. 1980 - 1983

Research

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 p...
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.

Publications

Journal Articles

Toxins targeting transfer RNAs: Translation inhibition by bacterial toxin-antitoxin systems.

Walling LR, Butler JS

Wiley interdisciplinary reviews. RNA.. 2019 January 10 (1):e1506. Epub 09/16/2018.

Homologous VapC Toxins Inhibit Translation and Cell Growth by Sequence-Specific Cleavage of tRNA.

Walling LR, Butler JS

Journal of bacteriology.. 2018 February 1200 (3)Epub 01/10/2018.

Structural Determinants for Antitoxin Identity and Insulation of Cross Talk between Homologous Toxin-Antitoxin Systems.

Walling LR, Butler JS

Journal of bacteriology.. 2016 December 15198 (24):3287-3295. Epub 11/18/2016.

Using S. cerevisiae as a Model System to Investigate V. cholerae VopX-Host Cell Protein Interactions and Phenotypes.

Seward CH, Manzella A, Alam A, Butler JS, Dziejman M

Toxins.. 2015 October 147 (10):4099-110. Epub 10/14/2015.

Structure-function analysis of VapB4 antitoxin identifies critical features of a minimal VapC4 toxin-binding module.

Jin G, Pavelka MS, Butler JS

Journal of bacteriology.. 2015 April 197 (7):1197-207. Epub 01/26/2015.

Analysis of non-typeable Haemophilous influenzae VapC1 mutations reveals structural features required for toxicity and flexibility in the active site.

Hamilton B, Manzella A, Schmidt K, DiMarco V, Butler JS

PloS one.. 2014 9 (11):e112921. Epub 11/12/2014.

Nuclear RNA surveillance: role of TRAMP in controlling exosome specificity.

Schmidt K, Butler JS

Wiley interdisciplinary reviews. RNA.. 2013 4 (2):217-31. Epub 02/15/2013.

Air proteins control differential TRAMP substrate specificity for nuclear RNA surveillance.

Schmidt K, Xu Z, Mathews DH, Butler JS

RNA.. 2012 October 18 (10):1934-45. Epub 08/24/2012.

Identification of Vibrio cholerae type III secretion system effector proteins.

Alam A, Miller KA, Chaand M, Butler JS, Dziejman M

Infection and immunity.. 2011 April 79 (4):1728-40. Epub 01/31/2011.

Rrp6, rrp47 and cofactors of the nuclear exosome.

Butler JS, Mitchell P

Advances in experimental medicine and biology.. 2011 702 :91-104. Epub 1900 01 01.

TRAMP complex enhances RNA degradation by the nuclear exosome component Rrp6.

Callahan KP, Butler JS

The Journal of biological chemistry.. 2010 February 5285 (6):3540-3547. Epub 12/02/2009.

Rrp6, Rrp47 and cofactors of the nuclear exosome.

Butler JS, Mitchell P

Advances in experimental medicine and biology.. 2010 702 :91-104. Epub 1900 01 01.

Regulation of NAB2 mRNA 3'-end formation requires the core exosome and the Trf4p component of the TRAMP complex.

Roth KM, Byam J, Fang F, Butler JS

RNA.. 2009 June 15 (6):1045-58. Epub 04/15/2009.

Evidence for core exosome independent function of the nuclear exoribonuclease Rrp6p.

Callahan KP, Butler JS

Nucleic acids research.. 2008 December 36 (21):6645-55. Epub 10/21/2008.

RNA-based 5-fluorouracil toxicity requires the pseudouridylation activity of Cbf5p.

Hoskins J, Butler JS

Genetics.. 2008 May 179 (1):323-30. Epub 1900 01 01.

Lifting the veil on the transcriptome.

Callahan KP, Butler JS

Genome biology.. 2008 9 (4):218. Epub 1900 01 01.

Rat1p and Rai1p function with the nuclear exosome in the processing and degradation of rRNA precursors.

Fang F, Phillips S, Butler JS

RNA.. 2005 October 11 (10):1571-8. Epub 08/30/2005.

The nuclear exosome contributes to autogenous control of NAB2 mRNA levels.

Roth KM, Wolf MK, Rossi M, Butler JS

Molecular and cellular biology.. 2005 March 25 (5):1577-85. Epub 1900 01 01.

5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs.

Fang F, Hoskins J, Butler JS

Molecular and cellular biology.. 2004 December 24 (24):10766-76. Epub 1900 01 01.

Polyadenylation of rRNA in Saccharomyces cerevisiae.

Kuai L, Fang F, Butler JS, Sherman F

Proceedings of the National Academy of Sciences of the United States of America.. 2004 June 8101 (23):8581-6. Epub 06/01/2004.

Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes.

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

Cell.. 2004 January 9116 (1):121-37. Epub 1900 01 01.

Contribution of domain structure to the RNA 3' end processing and degradation functions of the nuclear exosome subunit Rrp6p.

Phillips S, Butler JS

RNA.. 2003 September 9 (9):1098-107. Epub 1900 01 01.

Degradation of normal mRNA in the nucleus of Saccharomyces cerevisiae.

Das B, Butler JS, Sherman F

Molecular and cellular biology.. 2003 August 23 (16):5502-15. Epub 1900 01 01.

The yin and yang of the exosome.

Butler JS

Trends in cell biology.. 2002 February 12 (2):90-6. Epub 1900 01 01.

A nuclear 3'-5' exonuclease involved in mRNA degradation interacts with Poly(A) polymerase and the hnRNA protein Npl3p.

Burkard KT, Butler JS

Molecular and cellular biology.. 2000 January 20 (2):604-16. Epub 1900 01 01.

Rrp6p, the yeast homologue of the human PM-Scl 100-kDa autoantigen, is essential for efficient 5.8 S rRNA 3' end formation.

Briggs MW, Burkard KT, Butler JS

The Journal of biological chemistry.. 1998 May 22273 (21):13255-63. Epub 1900 01 01.

Regulation of tRNA suppressor activity by an intron-encoded polyadenylation signal.

Liang S, Briggs MW, Butler JS

RNA.. 1997 June 3 (6):648-59. Epub 1900 01 01.

Ribosome concentration contributes to discrimination against poly(A)- mRNA during translation initiation in Saccharomyces cerevisiae.

Proweller A, Butler JS

The Journal of biological chemistry.. 1997 February 28272 (9):6004-10. Epub 1900 01 01.

RNA polymerase III defects suppress a conditional-lethal poly(A) polymerase mutation in Saccharomyces cerevisiae.

Briggs MW, Butler JS

Genetics.. 1996 July 143 (3):1149-61. Epub 1900 01 01.

Ribosomal association of poly(A)-binding protein in poly(A)-deficient Saccharomyces cerevisiae.

Proweller A, Butler JS

The Journal of biological chemistry.. 1996 May 3271 (18):10859-65. Epub 1900 01 01.

Redundant 3' end-forming signals for the yeast CYC1 mRNA.

Guo Z, Russo P, Yun DF, Butler JS, Sherman F

Proceedings of the National Academy of Sciences of the United States of America.. 1995 May 992 (10):4211-4. Epub 1900 01 01.

Efficient translation of poly(A)-deficient mRNAs in Saccharomyces cerevisiae.

Proweller A, Butler S

Genes & development.. 1994 November 18 (21):2629-40. Epub 1900 01 01.

Conditional defect in mRNA 3' end processing caused by a mutation in the gene for poly(A) polymerase.

Patel D, Butler JS

Molecular and cellular biology.. 1992 July 12 (7):3297-304. Epub 1900 01 01.

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.

Sadhale PP, Sapolsky R, Davis RW, Butler JS, Platt T

Nucleic acids research.. 1991 July 1119 (13):3683-8. Epub 1900 01 01.

RNA processing in vitro produces mature 3' ends of a variety of Saccharomyces cerevisiae mRNAs.

Butler JS, Sadhale PP, Platt T

Molecular and cellular biology.. 1990 June 10 (6):2599-605. Epub 1900 01 01.

RNA processing generates the mature 3' end of yeast CYC1 messenger RNA in vitro.

Butler JS, Platt T

Science.. 1988 December 2242 (4883):1270-4. Epub 1900 01 01.

AUU-to-AUG mutation in the initiator codon of the translation initiation factor IF3 abolishes translational autocontrol of its own gene (infC) in vivo.

Butler JS, Springer M, Grunberg-Manago M

Proceedings of the National Academy of Sciences of the United States of America.. 1987 June 84 (12):4022-5. Epub 1900 01 01.

Escherichia coli protein synthesis initiation factor IF3 controls its own gene expression at the translational level in vivo.

Butler JS, Springer M, Dondon J, Graffe M, Grunberg-Manago M

Journal of molecular biology.. 1986 December 20192 (4):767-80. Epub 1900 01 01.

Genetic definition of the translational operator of the threonine-tRNA ligase gene in Escherichia coli.

Springer M, Graffe M, Butler JS, Grunberg-Manago M

Proceedings of the National Academy of Sciences of the United States of America.. 1986 June 83 (12):4384-8. Epub 1900 01 01.

Posttranscriptional autoregulation of Escherichia coli threonyl tRNA synthetase expression in vivo.

Butler JS, Springer M, Dondon J, Grunberg-Manago M

Journal of bacteriology.. 1986 January 165 (1):198-203. Epub 1900 01 01.

Autogenous control of Escherichia coli threonyl-tRNA synthetase expression in vivo.

Springer M, Plumbridge JA, Butler JS, Graffe M, Dondon J, Mayaux JF, Fayat G, Lestienne P, Blanquet S, Grunberg-Manago M

Journal of molecular biology.. 1985 September 5185 (1):93-104. Epub 1900 01 01.

Eucaryotic initiation factor 4B of wheat germ binds to the translation initiation region of a messenger ribonucleic acid.

Butler JS, Clark JM

Biochemistry.. 1984 February 2823 (5):809-15. Epub 1900 01 01.