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Tara Davis

Tara Davis, PhD

Assistant Professor


Department: Biochemistry & Molecular Biology

Education

  • PhD in Molecular Biophysics - University of Texas Southwestern Medical Center

Dr. Davis is an assistant professor in the Department of Biochemistry and Molecular Biology. Prior to joining the College of Medicine, she served as a post-doctoral researcher at the University of Toronto and the University of California – Santa Cruz.

Research Interests

RNA biology, structural biology, X-ray crystallography, pre-mRNA splicing.

Research

Splicing, the process by which introns are removed from pre-mRNA, is accomplished by the complex macromolecular machinery called the spliceosome. The spliceosome promotes the two trans-esterification reactions necessary to release intron sequence from the pre-mRNA substrate and join together flanking exons.  Splicing is a highly regulated process in humans, and point mutations in either the RNA or protein components of the splicing pathway are responsible for disease pathologies ranging from retinitis pigmentosa (RP) and spinal muscular atrophy (SMA) to involvement in a broad range of cancers.  It has been estimated that 60% of genetically encoded disease pathology is actually due to mis-splicing events rather than mistakes in coding regions of proteins. (López-Bigas et. al., 2005: PMID 15792793).

The spliceosome is composed of 5 uridine-rich small nuclear RNAs (U-snRNAs) and hundreds of proteins that dynamically assemble and disassemble within the spliceosome during the splicing cycle.  Although many of these proteins may be potential drug targets for therapeutic resolution of mis-splicing events, this effort is hampered by the lack of information about the function of these proteins within splicing.  An example of this is the cyclophilin family of peptidyl-prolyl isomerases.  There are 17 cyclophilins encoded in the human genome, and all 9 of the nuclear cyclophilins are found stably associated with spliceosomal complexes.  Cyclophilins are the target of the drug cyclosporine, and have also been extensively studied in vitro in terms of biochemistry and structural biology (Davis et. al., 2010: PMID 20676357), but their roles in the cellular milieu remain cryptic.  The Davis Lab at Drexel studies the role that the eight major nuclear cyclophilins play in spliceosome assembly and regulation of splicing chemistry.

Recent work has determined that the nuclear cyclophilins exert unique effects on spliceosome assembly and splicing chemistry (Davis et. al., manuscript submitted).  In order to understand the mechanism by which cyclophilins function within the spliceosome, projects designed to tease out the protein:protein interaction network within the spliceosome have been designed.  By utilizing yeast two-hybrid assays, our lab and others have determined that each of the nuclear cyclophilins interact with a unique set of splicing factors.  We are now in the process of verifying these unique interactions for individual cyclophilins, both by utilizing directed yeast two-hybrid assays and by co-immunoprecipitation (Co-IP) of cyclophilins out of human nuclear extracts.  Additionally, we are using ligation-independent cloning (LIC) techniques to clone and screen for soluble expression constructs for cyclophilin-interacting splicing factors, with the eventual goal of structural determination via x-ray crystallography.  Individual projects will focus on a single cyclophilin and its potential interaction network.  By identifying, validating, and co-crystallizing nuclear cyclophilins with their partners in the spliceosome, we will be able to define unique pathways for regulating mRNA splicing and potentially develop new drugs to treat splicing-related pathologies.
 

Publications

View all of Tara Davis's publications

"Development of Fluorescent Substrates and Assays for the Key Autophagy-Related Cysteine Protease Enzyme, ATG4B"
*Nguyen TG, Honson NS, Arns S, Davis TL, Dhe-Paganon S, Kovacic S, Kumar NS, Pfeifer TA, Young RN.
Assay Drug Dev. Technol.; 12(3), April 2014.

"The Human Cyclophilin Family of Peptidyl-Prolyl Isomerases"
Davis TL, Walker JR, Campagna-Slater V, Finerty Jr. PJ, Paramanathan R, Bernstein G, Tempel W, Ouyang H, Lee, WH, Eisenmesser E, Dhe-Paganon S
PLoS Biology; 8(7) , July 2010.

"A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation"
*Littler DR, Walker JR, Davis T, Wybenga-Groot LE, Finerty PJ Jr, Newman E, Mackenzie F, Dhe-Paganon S
Acta Crystallogr Sect F Struct Biol Cryst Commun.;66(Pt 2):143-51, Feb 1 2010.

"Structural recognition of an optimized substrate for the ephrin family of receptor tyrosine kinases"
Davis TL, Walker JR, Allali-Hassani A, Parker, SA, Turk, BE, Dhe-Paganon S
FEBS Journal;276(16):4395-404, Aug 2009.

"Structure of Human Pancreatic Lipase-Related Protein 2 with the Lid in an Open Conformation"
*Eydoux C, Spinelli S, Davis TL, Walker JR, Seitova A, Dhe-Paganon S, De Caro A, Cambillau C, Carrie`re F
Biochemistry;47(36):9553-64, Sep 9, 2008.

"Autoregulation by the Juxtamembrane Region of the Human Ephrin Receptor Tyrosine Kinase A3 (EPHA3)"
Davis TL, Walker JR, Loppnau P, Butler-Cole C, Allali-Hassani A, Dhe-Paganon S
Structure;16(6):873-84, Jun 2008.

"The crystal structure of human WD40 repeat-containing peptidylprolyl isomerase (PPWD1)"
Davis TL, Walker JR, Ouyang H, Mackenzie F, Butler-Cole C, Newman EM, Eisenmesser EZ, Dhe-Paganon S
FEBS Journal;275(9):2283-95, May 2008.

"Structural, biochemical, and in vivo characterization of the first virally encoded cyclophilin from the Mimivirus"
*Thai V, Renesto P, Fowler CA, Brown DJ, Davis T, Gu W, Pollock DD, Kern D, Raoult D, Eisenmesser EZ
J Mol Biol.;378(1):71-86, April 18, 2008.

"The crystal structures of human calpains 1 and 9 imply diverse mechanisms of action and auto-inhibition"
Davis TL, Walker JR, Finerty PJ Jr, Mackenzie F, Newman EM, Dhe-Paganon S
Journal of Molecular Biology;366(1):216-29, Feb 9 2007.

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Contact Information


Research Office

Department of Biochemistry & Molecular Biology
245 North 15th Street
Mail Stop 497
Philadelphia, PA 19102
Phone: 215.762.4234