Joel W. Hockensmith

Education

  • BS, Philadelphia College of Pharmacy and Science
  • PhD, University of Rochester

Primary Appointment

  • Associate Professor, Biochemistry and Molecular Genetics

Contact

Research Interest(s)

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Research Description

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The advent of drug-resistant strains of bacteria and protozoans is expected to exacerbate the already heavy toll parasitic diseases exact on human life and health. Development of new paradigms for controlling these parasites is important and may come through a basic understanding of DNA metabolic events. Our extensive biochemical analysis of a nuclear enzyme's interactions with DNA has led to the discovery of a mechanism to disrupt ATP-dependent DNA metabolic events. Antibiotic-resistant bacteria are the source of potent, naturally occurring inhibitors of eukaryotic DNA-dependent ATPase activity. These are the first reported inhibitors that are specific for DNA-dependent ATP hydrolysis. The DNA-dependent ATPase domain targeted by these inhibitors is found in proteins that play integral roles in many DNA metabolic processes; including DNA replication, transcription, repair, recombination and histone remodeling. Three inhibitors have been demonstrated to be toxic to protozoans (Plasmodium falciparum (Malaria), Entamoeba histolytica, Leishmania chagasi) but not bacteria. Five additional inhibitors have been prepared and demonstrated to be inhibitory for the nuclear enzyme in vitro. The eight derivatives range widely in potency (50-fold) and are generally more than a thousand-fold more potent than the parent antibiotic. The targeting of specific nuclear enzymes leading to disruption of the protozoan life cycle provides an exciting development in the treatment of protozoan diseases. We are attempting to expand and refine our understanding of DNA metabolic events in protozoans and to evaluate mechanisms that could lead to the death of protozoans. Our studies aim to facilitate the development of DNA-dependent ATPase inhibitor species specific for protozoan growth.

Selected Publications

  • Dutta P, Tanti G, Sharma S, Goswami S, Komath S, Mayo M, Hockensmith J, Muthuswami R. Global Epigenetic Changes Induced by SWI2/SNF2 Inhibitors Characterize Neomycin-Resistant Mammalian Cells. PloS one. 2012;7(11): e49822. PMID: 23209606 | PMCID: PMC3509132
  • Nongkhlaw M, Dutta P, Hockensmith J, Komath S, Muthuswami R. Elucidating the mechanism of DNA-dependent ATP hydrolysis mediated by DNA-dependent ATPase A, a member of the SWI2/SNF2 protein family. Nucleic acids research. 2009;37(10): 3332-41. PMID: 19324887 | PMCID: PMC2691824
  • Singh U, Gilchrist C, Schaenman J, Rogers J, Hockensmith J, Mann B, Petri W. Context-dependent roles of the Entamoeba histolytica core promoter element GAAC in transcriptional activation and protein complex assembly. Molecular and biochemical parasitology. 2002;120(1): 107-16. PMID: 11849710
  • Muthuswami R, Mesner L, Wang D, Hill D, Imbalzano A, Hockensmith J. Phosphoaminoglycosides inhibit SWI2/SNF2 family DNA-dependent molecular motor domains. Biochemistry. 2000;39(15): 4358-65. PMID: 10757984
  • Muthuswami R, Truman P, Mesner L, Hockensmith J. A eukaryotic SWI2/SNF2 domain, an exquisite detector of double-stranded to single-stranded DNA transition elements. The Journal of biological chemistry. 2000;275(11): 7648-55. PMID: 10713074
  • Schaenman J, Driscoll P, Hockensmith J, Mann B, Petri W. An upstream regulatory element containing two nine basepair repeats regulates expression of the Entamoeba histolytica hgl5 lectin gene. Molecular and biochemical parasitology. 1998;94(2): 309-13. PMID: 9747982
  • Hockensmith J, Kubasek W, Vorachek W, von Hippel P. Laser cross-linking of proteins to nucleic acids. I. Examining physical parameters of protein-nucleic acid complexes. The Journal of biological chemistry. 1993;268(21): 15712-20. PMID: 8340395
  • Mesner L, Sutherland W, Hockensmith J. DNA-dependent adenosinetriphosphatase A is the eukaryotic analogue of the bacteriophage T4 gene 44 protein: immunological identity of DNA replication-associated ATPases. Biochemistry. 1991;30(49): 11490-4. PMID: 1720977
  • Hockensmith J, Wahl A, Kowalski S, Bambara R. Purification of a calf thymus DNA-dependent adenosinetriphosphatase that prefers a primer-template junction effector. Biochemistry. 1986;25(24): 7812-21. PMID: 3026461