Tony R. Hazbun

Publication Listings

ResearchGate | Google Scholar

The research philosophy of the Hazbun lab is to approach biological questions from a network perspective and also utilize traditional scientific reductionist approaches to dissect and understand biological phenomena and mechanisms. Our research program uses systemwide approaches in yeast to investigate biological pathways involved in mitosis and cellular homeostasis related to human disease. We also use chemogenomic profiling to identify antifungal targets and characterize fungal gut metabolomics. In addition to these approaches we also use conventional biochemical, genetic and biophysical approaches to validate and interrogate the cellular network nodes and connections.

The lab currently has three major areas of research:

• Functional investigation of the N-terminal methyltransferome

• Chemogenomic profiling of small molecules and identification of antifungal targets

• Metabolomics of the gut fungal mycobiome

Significance of N-terminal methylation

• N-terminal methyltransferase (NRMT1 and NRMT2) mutations are found in cancers including endometrial, lung and breast cancer

• NTMT1 is overexpressed in several cancers in at least colorectal adenocarcinoma and malignant melanoma

• Loss of methylation of substrate proteins results in genome stability and impaired DNA repair pathways eg.RCC1, a regulator of chromatin condensation and DDB2, a DNA repair protein

• Biological knowledge is very narrow and we need a global picture to aid in selective targeting of this pathway for therapeutic applications

Why investigate N-terminal methylation in yeast?

• An opportunity to define the N-terminal methylome of all 45 potential substrates
• Systemwide approaches and resource are readily available
• Genetically and biochemically facile organism for mechanistic investigations
• Highly conserved enzyme mechanism and recognition motif

Chemogenomic Profiling

• Haploinsufficiency (HIP): identification of direct targets - gene dosage in each strain is at 50% and further small molecule inhibition of the reduced gene product results in preferential sensitivity

• Homozygous deletion profiling (HOP): identification of buffering pathways based on sensitivity or resistance of these homozygous deletion strains.

Targets Identified by Hazbun lab using Chemogenomics

• Ebselen – glutathione and ROS production
• Auranofin – Mia40 mitochondrial disulfide relay substrate folding
• Novel dibromoquinoline – metal ion homeostasis
• Symmetrical molecule with a bisphenol A core – Hsp90 inhibitor

• Mitosis and Cancer
• Chromosome segregation
• Aurora kinases
• Chaperone biology
• Hsp90
• Hsp31
• Chemogenomics identification of antifungal compounds

• MCMP 422 - Immunology
• PHRM 825 Professional Program Laboratory II Antibody-based diagnostic tests

Positions and Employment

1998-2005       Howard Hughes Medical Institute, Postdoctoral Associate, University of Washington

2001-2005       Two-hybrid Screening Coordinator, Yeast Resource Center (NCRR), University of Washington

2005-2011       Assistant Professor of Medicinal Chemistry and Molecular Pharmacology, Purdue University

2005-present  Full Member of the Bindley Bioscience Center, Discovery Park, Purdue University

2011-present  Associate Professor of Medicinal Chemistry and Molecular Pharmacology, Purdue University

Other Experience and Professional Memberships

1994-1997       Teaching Assistant, Department of Biology, University of Notre Dame 

2003                Future Faculty Fellows program, HHMI sponsored workshop

2005-present  Instructor – Immunology for Pharm.D. students

2005-present  Instructor – Cell Cycle and Drug Discovery for Graduate Students

Professional memberships Genetics Society of America, ABMB

Ad hoc reviewing activities

Reviewed for Nature Biotechnology, Biochemistry, PNAS, PLoS Genetics, PLoS Pathogens, PLoS One, Protein Science, Genome Biology, Cold Spring Harbor Laboratories Protocol, Biotechniques, Bioinformatics, Assay Development and Technologies, Genes Genomes and Genetics (G3), Methods, Wiley Encyclopedia of Chemical Biology.

Reviewed grants for:
National Institute of Health (NIH) – Genomics, Computational Biology and Technology Study Section

National Science Foundation (NSF)

Biomedical Research Council A*STAR – Singapore

Civilian Research and Development Foundation (CRDF)

New Zealand Ministry of Science and Innovation (MSI)

Faculty Chair for Computational Interdisciplinary Graduate Program

PULSe Computational and Systems Biology Training Group Chair

MCMP Graduate Admissions Committee Chair

1.         Guinan J, Wang S, Hazbun TR, Yadav H, Thangamani S. Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids correlate with increased gastrointestinal colonization of Candida albicans. Scientific Reports. 2019;9(1):8872.

2.         Chen C, Zhang D, Hazbun TR, Zhang M. Inferring Gene Regulatory Networks from a population of Yeast segregants. Scientific reports. 2019;9(1):1197.

3.         Mohammad H, Elghazawy NH, Eldesouky HE, Hegazy YA, Younis W, Avrimova L, et al. Discovery of a novel dibromoquinoline compound exhibiting potent antifungal and antivirulence activity that targets metal ion homeostasis. ACS infectious diseases. 2018;4(3):403-14.

4.         Mishra PK, Thapa KS, Chen P, Wang S, Hazbun TR, Basrai MA. Budding yeast CENP-ACse4 interacts with the N-terminus of Sgo1 and regulates its association with centromeric chromatin. Cell Cycle. 2018;17(1):11-23.

5.         Eldesouky HE, Mayhoub A, Hazbun TR, Seleem MN. Reversal of azole resistance in Candida albicans by sulfa antibacterial drugs. Antimicrobial agents and chemotherapy. 2018;62(3):e00701-17.

6.         Buehl CJ, Deng X, Luo J, Buranasudja V, Hazbun T, Kuo M-H. A failsafe for sensing chromatid tension in mitosis with the histone H3 tail in Saccharomyces cerevisiae. Genetics. 2018;208(2):565-78.

7.         Thomas FM, Goode KM, Rajwa B, Bieberich AA, Avramova LV, Hazbun TR, et al. A Chemogenomic Screening Platform Used to Identify Chemotypes Perturbing HSP90 Pathways. SLAS DISCOVERY: Advancing Life Sciences R&D. 2017;22(6):706-19.

8.         Thangamani S, Maland M, Mohammad H, Pascuzzi PE, Avramova L, Koehler CM, et al. Repurposing approach identifies auranofin with broad spectrum antifungal activity that targets Mia40-Erv1 pathway. Frontiers in cellular and infection microbiology. 2017;7:4.

9.         Thangamani S, Eldesouky HE, Mohammad H, Pascuzzi PE, Avramova L, Hazbun TR, et al. Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells. Biochimica et Biophysica Acta (BBA)-General Subjects. 2017;1861(1):3002-10.

10.       Goode KM, Petrov DP, Vickman RE, Crist SA, Pascuzzi PE, Ratliff TL, et al. Targeting the Hsp90 C-terminal domain to induce allosteric inhibition and selective client downregulation. Biochimica et Biophysica Acta (BBA)-General Subjects. 2017;1861(8):1992-2006.

11.       Wang S, Gribskov M, Hazbun TR, Pascuzzi PE. CellMiner Companion: an interactive web application to explore CellMiner NCI-60 data. Bioinformatics. 2016;32(15):2399-401.

12.       Aslam K, Tsai C-j, Hazbun TR. The small heat shock protein Hsp31 cooperates with Hsp104 to modulate Sup35 prion aggregation. Prion. 2016;10(6):444-65.

13.       Aslam K, Hazbun TR. Hsp31, a member of the DJ-1 superfamily, is a multitasking stress responder with chaperone activity. Prion. 2016;10(2):103-11.

14.       Tsai C-j, Aslam K, Drendel HM, Asiago JM, Goode KM, Paul LN, et al. Hsp31 is a stress response chaperone that intervenes in the protein misfolding process. Journal of Biological Chemistry. 2015;290(41):24816-34.

15.       Thapa KS, Oldani A, Pagliuca C, De Wulf P, Hazbun TR. The Mps1 kinase modulates the recruitment and activity of Cnn1CENP-T at Saccharomyces cerevisiae kinetochores. Genetics. 2015;200(1):79-90.

16.       Song B, Liu XS, Rice SJ, Kuang S, Elzey BD, Konieczny SF, et al. Plk1 phosphorylation of orc2 and hbo1 contributes to gemcitabine resistance in pancreatic cancer. Molecular cancer therapeutics. 2013;12(1):58-68.

17.       Bock LJ, Pagliuca C, Kobayashi N, Grove RA, Oku Y, Shrestha K, et al. Cnn1 inhibits the interactions between the KMN complexes of the yeast kinetochore. Nature Cell Biology. 2012;14(6):614.

18.       Luo J, Xu X, Hall H, Hyland EM, Boeke JD, Hazbun T, et al. Histone h3 exerts a key function in mitotic checkpoint control. Molecular and cellular biology. 2010;30(2):537-49.

19.       Wong J, Nakajima Y, Westermann S, Shang C, Kang J-s, Goodner C, et al. A protein interaction map of the mitotic spindle. Molecular biology of the cell. 2007;18(10):3800-9.

20.       Jin F, Avramova L, Huang J, Hazbun T. A yeast two-hybrid smart-pool-array system for protein-interaction mapping. Nature methods. 2007;4(5):405.

21.       Montpetit B, Hazbun TR, Fields S, Hieter P. Sumoylation of the budding yeast kinetochore protein Ndc10 is required for Ndc10 spindle localization and regulation of anaphase spindle elongation. The Journal of cell biology. 2006;174(5):653-63.

22.       Guo D, Hazbun TR, Xu X-J, Ng S-L, Fields S, Kuo M-H. A tethered catalysis, two-hybrid system to identify protein-protein interactions requiring post-translational modifications. Nature biotechnology. 2004;22(7):888.

23.       Shang C, Hazbun TR, Cheeseman IM, Aranda J, Fields S, Drubin DG, et al. Kinetochore protein interactions and their regulation by the Aurora kinase Ipl1p. Molecular biology of the cell. 2003;14(8):3342-55.

24.       Hazbun TR, Malmström L, Anderson S, Graczyk BJ, Fox B, Riffle M, et al. Assigning function to yeast proteins by integration of technologies. Molecular cell. 2003;12(6):1353-65.