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Genes & Development Graduate Program

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RICHARD G. BRENNAN, PH.D.
Professor

Department of Biochemistry and Molecular Biology
Room: S7.8336C  
Telephone: 713-834-6390
e-mail: rgbrenna@mdanderson.org

Research interests

  • multidrug resistance
  • gene regulation
  • protein-ligand interaction
  • X-ray crystallography
 

The overarching goal of the Brennan laboratory is to understand gene regulation at its most fundamental level.  Such understanding requires the complete delineation of the structural and biochemical mechanisms of ligand binding or reversible chemical modifications of a number of transcriptional regulators.  Thus, these regulatory proteins act as direct environmental sensors and effect changes in the genetic program of the cell in order to respond to the presence of specific cytoplasmic signals or stresses.  To date, we have solved the crystal structures of a number of transcription regulators and biologically germane protein-ligand complexes including PurR, which senses the levels of purines in the cell, bound to small molecule corepressors and DNA, a CREB bZIP-DNA complex and CcpA bound to the phosphoprotein HPr(Ser46P) and a catabolite responsive element.  The latter multiprotein-DNA structure has elucidated the mechanism of carbon catabolite regulation (CCR) in bacilli and opened avenues to exploit CCR as a novel drug target.  One key stress response, which is particularly relevant to human health, is the defence that cells muster upon their exposure to multiple drugs.  The emergence of multidrug resistant (mdr) bacteria, fungi and tumour cells, has resulted in the failure of a number of chemotherapeutics to treat infections and certain cancers.  In order to understand the origins of multidrug resistance, we are carrying out a number of biochemical and crystallographic studies on the multidrug binding transcription regulators, QacR, BmrR, MtrR and NfxB that will elucidate their DNA and multidrug binding mechanisms, and hence their modes of mdr gene regulation.  As a logical extension, we have begun similar studies on several multidrug efflux transporters with the long-term goal of developing structure-based antibacterial chemotherapeutics.  Work on HIF-1, Spx, OhrR and PerR will reveal the transcriptional responses of mammals to hypoxia, which is key for tumour growth, and bacteria to oxidative stress, which allow them to overcome the killing effects of peroxides and superoxide anions.  Finally, we are interested in unveiling the mechanisms of post transcriptional gene regulation by small noncoding RNAs.  To do so, we are carrying out structure-function studies on Hfq, the ubiquitous, pleiotropic regulator of translation and mRNA stability, and its physiologically relevant RNA complexes.


Recent publications
  • Amen M, Espinoza HM, Cox C, Liang X, Wang J, Link TM, Brennan RG, Martin JF, Amendt BA (2008) Chromatin-Associated HMG-17 is a Major Regulator of Homeodomain Transcription Factor Activity Modulated by Wnt/b-catenin Signalling. Nucl. Acids Res. 36: 462–476.
  • Shelburne III SA, Keith D, Horstmann N, Sumby P, Davenport MT, Graviss EA, Brennan RG, Musser JM (2008) A direct link between carbohydrate utilization and virulence in the major human pathogen group A Streptococcus. Proc. Natl. Acad Sci., U.S.A. (in press).
  • Newberry KJ, Fuangthong M, Panmanee W, Mongkolsuk S, Brennan RG (2007) Structural Mechanism of Organic Hydroperoxide Induction of the Transcription Regulator OhrR. Mol. Cell 28: 652–664).
  • Brooks BE, Piro KM, Brennan RG (2007) The Multidrug-Binding Transcription Factor, QacR, Binds the Bivalent Aromatic Diamidines DB75 and DB359 in Multiple Positions. J. Amer. Chem. Soc. 129: 8389–8395.
  • Brennan RG, Link TM (2007) Hfq Structure, Function and Ligand Binding. Curr. Opin. Microbiol. 10: 125–133.
  • Schumacher MA, Seidel G, Hillen W, Brennan RG (2006) Phosphoprotein Crh-Ser-46-P displays altered binding to CcpA to effect carbon catabolite regulation. J. Biol. Chem. 281: 6793–6780.

  • Newberry KJ, Nakano S, Zuber P, Brennan RG (2005) Crystal structure of the Bacillus subtilis anti alpha, global transcriptional regulator, Spx, in complex with the a C-terminal domain of RNA polymerase. Proc. Natl. Acad. Sci., U.S.A. (Track II) 102: 15839–15844.
  • Hong M, Fuangthong M, Helmann JD, Brennan RG (2005) Structure of an OhrR-ohrA operator complex reveals the DNA binding mechanism of the MarR family. Mol. Cell 20: 131–141.
  • Newberry KJ, Brennan RG (2004) The Structural Mechanism of Transcription Activation by MerR Family Member MtaN. J. Biol. Chem., 279: 20356–20362.

  • Schumacher MA, Miller RF, Møller T, Valentin-Hansen P, Brennan RG (2002) Structures of the pleiotropic translational regulator Hfq and an Hfq-RNA complex; a bacterial Sm-like protein. EMBO J., 21: 3546–3556.

  • Schumacher MA, Miller MC, Grkovic S, Brown MH, Skurray RA, Brennan RG (2002) Structural basis for cooperative DNA binding by two dimers of the multidrug binding protein QacR. EMBO J. 21: 1210–1218.
  • Schumacher MA, Miller MC, Grkovic S, Brown MH, Skurray RA, Brennan RG (2001) Structural Mechanisms of QacR Induction and Multidrug Recognition. Science, 294: 2158–2163.

  • Zheleznova Heldwein, EE, Brennan RG (2001) Crystal structure of the transcription activator BmrR bound to DNA and a drug. Nature, 409: 378–382.

Mailing Address:
Department of Biochemistry and Molecular Biology, Unit 1000
U.T. M.D. Anderson Cancer Center
1515 Holcombe Boulevard
Houston, TX 77030

Last updated 02/06/2008