Neil Osheroff, Ph.D.

Official Affiliation: Medicine

Profile

The intertwining of the two strands of the DNA helix presents a number of topological problems that the cell must be able to overcome in order to maintain its genetic information. Consequently, the enzymes that modulate the topological state of nucleic acids play a crucial role in controlling the physiological functions of DNA.

In the cell, the topological structure of DNA is modulated by ubiquitous enzymes known as topoisomerases. The type II enzyme alters nucleic acid topology by passing an intact double helix of DNA through a transient double-stranded break made in a second DNA helix. In vivo, it is involved in DNA replication, recombination, and chromosome segregation. In addition, topoisomerase II plays important roles in chromosome structure. Beyond its normal cellular activities, the enzyme is the primary target for some of the most active drugs currently used for the treatment of human cancers. Despite the importance of topoisomerase II to the eukaryotic cell and to cancer chemotherapy, there is relatively little understood about its mechanism of action or those of topoisomerase II-targeted drugs.


The goal of my laboratory is to define the function and biology of eukaryotic topoisomerase II. To this end, four broad-based projects are currently underway. First, the enzymatic mechanism, active sites, and structure of topoisomerase II are being characterized. Current studies have delineated a number of individual steps in the catalytic cycle of the enzyme. Second, the mechanism by which chemotherapeutic drugs act on topoisomerase II is being explored. Work in this area has contributed to our understanding of drug action and also has identified at least two novel classes of potential anticancer agents. Third, the mechanism(s) by which topoisomerase II becomes resistant or hypersensitive to anticancer drugs is being addressed. In support of this project, a number of mutant type II topoisomerases with altered drug sensitivity have been isolated and are being characterized. Fourth, interactions between topoisomerase II and DNA lesions are being investigated. Initial work indicates that the enzyme interacts with specific forms of DNA damage and that lesions alter topoisomerase II activity in a manner similar to that of anticancer drugs. These findings indicate a novel physiological function for topoisomerase II and a mechanism by which the enzyme can selectively remove damaged cells from a population. Furthermore, it provides a teleological thread that links the chemotherapeutic actions of clinically relevant anticancer drugs to a natural cellular process.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Mechanism of quinolone action and resistance. Aldred KJ, Kerns RJ, Osheroff N (2014) Biochemistry 53(10): 1565-74
    › Primary publication · 24576155 (PubMed) · PMC3985860 (PubMed Central)
  2. Topoisomerase II and leukemia. Pendleton M, Lindsey RH, Felix CA, Grimwade D, Osheroff N (2014) Ann N Y Acad Sci : 98-110
    › Primary publication · 24495080 (PubMed) · PMC3961513 (PubMed Central)
  3. Chiral discrimination and writhe-dependent relaxation mechanism of human topoisomerase IIα. Seol Y, Gentry AC, Osheroff N, Neuman KC (2013) J Biol Chem 288(19): 13695-703
    › Primary publication · 23508957 (PubMed) · PMC3650406 (PubMed Central)
  4. Structure of a topoisomerase II-DNA-nucleotide complex reveals a new control mechanism for ATPase activity. Schmidt BH, Osheroff N, Berger JM (2012) Nat Struct Mol Biol 19(11): 1147-54
    › Primary publication · 23022727 (PubMed) · PMC3492516 (PubMed Central)
  5. DNA cleavage and opening reactions of human topoisomerase IIα are regulated via Mg2+-mediated dynamic bending of gate-DNA. Lee S, Jung SR, Heo K, Byl JA, Deweese JE, Osheroff N, Hohng S (2012) Proc Natl Acad Sci U S A 109(8): 2925-30
    › Primary publication · 22323612 (PubMed) · PMC3286967 (PubMed Central)
  6. Molecular pathogenesis of secondary acute promyelocytic leukemia. Joannides M, Mays AN, Mistry AR, Hasan SK, Reiter A, Wiemels JL, Felix CA, Coco FL, Osheroff N, Solomon E, Grimwade D (2011) Mediterr J Hematol Infect Dis 3(1): e2011045
    › Primary publication · 22110895 (PubMed) · PMC3219647 (PubMed Central)
  7. Etoposide quinone is a redox-dependent topoisomerase II poison. Jacob DA, Mercer SL, Osheroff N, Deweese JE (2011) Biochemistry 50(25): 5660-7
    › Primary publication · 21595477 (PubMed) · PMC3119725 (PubMed Central)
  8. Direct measurement of DNA bending by type IIA topoisomerases: implications for non-equilibrium topology simplification. Hardin AH, Sarkar SK, Seol Y, Liou GF, Osheroff N, Neuman KC (2011) Nucleic Acids Res 39(13): 5729-43
    › Primary publication · 21421557 (PubMed) · PMC3141238 (PubMed Central)
  9. First ruthenium organometallic complex of antibacterial agent ofloxacin. Crystal structure and interactions with DNA. Turel I, Kljun J, Perdih F, Morozova E, Bakulev V, Kasyanenko N, Byl JA, Osheroff N (2010) Inorg Chem 49(23): 10750-2
    › Primary publication · 20973588 (PubMed) · PMC3698415 (PubMed Central)
  10. The geometry of DNA supercoils modulates the DNA cleavage activity of human topoisomerase I. Gentry AC, Juul S, Veigaard C, Knudsen BR, Osheroff N (2011) Nucleic Acids Res 39(3): 1014-22
    › Primary publication · 20855291 (PubMed) · PMC3035449 (PubMed Central)
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Contact Information

654 Robinson Research Building
Department of Biochemistry Vanderbilt University School of Medicine
Nashville, TN 37232
USA
615-322-4338 (p)
Email

Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

Adenosine Triphosphatases Anti-Infective Agents Antigens, Neoplasm Azides Bioterrorism Carrier Proteins Cellulose Chromatography, DEAE-Cellulose Computers DNA, Neoplasm DNA, Single-Stranded DNA Repair Drug Resistance, Microbial Female Flavonols Fluoroquinolones Genes, Fungal Isomerism Lipoproteins Microscopy, Electron Molecular Biology Molecular Weight Myeloid-Lymphoid Leukemia Protein Nitrophenols Phosphorus Radioisotopes Rhabdomyosarcoma, Alveolar RNA, Viral Saccharomyces cerevisiae Sequence Analysis, DNA Transcriptional Elongation Factors