FUNCTION AND BIOLOGY OF EUKARYOTIC DNA TOPOISOMERASES

Summary

Principal Investigator: Neil Osheroff
Abstract: DESCRIPTION (provided by applicant): Type II topoisomerases are ubiquitous enzymes that are required for proper chromosome structure and segregation and play important roles in DNA replication, transcription, and recombination. Type II topoisomerases relax DNA and remove knots and tangles from the genetic material by passing an intact double helix (transport segment) through a transient double-stranded break that they generate in a separate DNA segment (gate segment). Humans encode two closely related isoforms of the type II enzyme, topoisomerase II[unreadable] and topoisomerase II[unreadable]. Topoisomerase II[unreadable] is essential for the survival of proliferating cells and topoisomerase II[unreadable] plays critical roles during development. However, because these enzymes generate requisite double-stranded DNA breaks during their crucial catalytic functions, they assume a dual persona. Although essential to cell survival, they also pose an intrinsic threat to genomic integrity every time they act. Beyond their critical physiological functions, topoisomerase II[unreadable] and II[unreadable] are the primary targets for some of the most active and widely prescribed drugs currently used for the treatment of human cancers. These agents kill cells by increasing levels of covalent topoisomerase II-cleaved DNA complexes that are normal, but fleeting, intermediates in the catalytic DNA strand passage reaction. Most clinically relevant drugs do so by inhibiting the ability of the type II enzymes to ligate cleaved DNAs. When the resulting enzyme-associated DNA breaks are present in sufficient concentrations, they can trigger cell death pathways. Anticancer drugs that target type II enzymes are referred to as topoisomerase II poisons because they convert these indispensable enzymes to potent physiological toxins that generate DNA damage in treated cells. Although topoisomerase II[unreadable] and II[unreadable] are important targets for cancer chemotherapy, evidence suggests that they also have the potential to trigger specific leukemias. A small percentage of cancer (and other) patients treated with topoisomerase II-targeted drugs eventually develop acute myeloid leukemias (AMLs) involving the MLL gene at chromosome band 11q23 or acute promyelocytic leukemias involving 15:17 translocations. The 11q23 chromosomal translocations also are seen in infant AMLs, and the risk of these leukemias rises ~3-fold when there is high maternal exposure during pregnancy to environmental and dietary topoisomerase II poisons. Despite the importance of the type II enzymes to cell growth and cancer, interactions between human topo- isomerase II and DNA, anticancer drugs, and other topoisomerase II poisons have not been well characterized. Thus, the aims of this proposal are to further define the catalytic mechanism of topoisomerase II, to further delineate the mechanism by which topoisomerase poisons increase levels of enzyme-mediated DNA breaks, and to determine the cellular consequences of topoisomerase II poisons. The primary research model for this study will be human topoisomerase II[unreadable] and II[unreadable]. Bacillus anthracis gyrase and topoisomerase IV will be used for some experiments to provide comparisons between the prokaryotic and eukaryotic type II enzymes.
Funding Period: 1984-07-01 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc Etoposide quinone is a covalent poison of human topoisomerase IIβ
    Nicholas A Smith
    Departments of Biochemistry, Medicine Hematology Oncology, and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 53:3229-36. 2014
  2. pmc Contributions of the D-Ring to the activity of etoposide against human topoisomerase IIα: potential interactions with DNA in the ternary enzyme--drug--DNA complex
    Steven L Pitts
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 50:5058-66. 2011
  3. pmc Direct measurement of DNA bending by type IIA topoisomerases: implications for non-equilibrium topology simplification
    Ashley H Hardin
    Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Nucleic Acids Res 39:5729-43. 2011
  4. pmc Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage
    Amanda C Gentry
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 50:3240-9. 2011
  5. pmc Use of divalent metal ions in the DNA cleavage reaction of topoisomerase IV
    Steven L Pitts
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Nucleic Acids Res 39:4808-17. 2011
  6. pmc First ruthenium organometallic complex of antibacterial agent ofloxacin. Crystal structure and interactions with DNA
    Iztok Turel
    Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
    Inorg Chem 49:10750-2. 2010
  7. pmc The geometry of DNA supercoils modulates the DNA cleavage activity of human topoisomerase I
    Amanda C Gentry
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Nucleic Acids Res 39:1014-22. 2011
  8. pmc The use of divalent metal ions by type II topoisomerases
    Joseph E Deweese
    Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, TN 37204 3951, USA
    Metallomics 2:450-9. 2010
  9. pmc A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases
    Bryan H Schmidt
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
    Nature 465:641-4. 2010
  10. pmc Metnase promotes restart and repair of stalled and collapsed replication forks
    Leyma P De Haro
    Department of Molecular Genetics and Microbiology, Division of Hematology Oncology, Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
    Nucleic Acids Res 38:5681-91. 2010

Research Grants

Detail Information

Publications54

  1. pmc Etoposide quinone is a covalent poison of human topoisomerase IIβ
    Nicholas A Smith
    Departments of Biochemistry, Medicine Hematology Oncology, and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 53:3229-36. 2014
    ..These results are consistent with the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis through an interaction with topoisomerase IIβ...
  2. pmc Contributions of the D-Ring to the activity of etoposide against human topoisomerase IIα: potential interactions with DNA in the ternary enzyme--drug--DNA complex
    Steven L Pitts
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 50:5058-66. 2011
    ..On the basis of these findings, we propose that the D-ring of etoposide has important interactions with DNA in the ternary topoisomerase II cleavage complex...
  3. pmc Direct measurement of DNA bending by type IIA topoisomerases: implications for non-equilibrium topology simplification
    Ashley H Hardin
    Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
    Nucleic Acids Res 39:5729-43. 2011
    ..These data suggest that DNA bending is not the sole determinant of non-equilibrium topology simplification. Rather, they suggest a fundamental and conserved role for DNA bending in the enzymatic cycle of type IIA topoisomerases...
  4. pmc Interactions between the etoposide derivative F14512 and human type II topoisomerases: implications for the C4 spermine moiety in promoting enzyme-mediated DNA cleavage
    Amanda C Gentry
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 50:3240-9. 2011
    ..These findings demonstrate the utility of a C4 DNA binding group and provide a rational basis for the development of novel and more active etoposide-based topoisomerase II poisons...
  5. pmc Use of divalent metal ions in the DNA cleavage reaction of topoisomerase IV
    Steven L Pitts
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Nucleic Acids Res 39:4808-17. 2011
    ....
  6. pmc First ruthenium organometallic complex of antibacterial agent ofloxacin. Crystal structure and interactions with DNA
    Iztok Turel
    Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
    Inorg Chem 49:10750-2. 2010
    ..Our experiments revealed that binding of the title complex to DNA occurs also if guanine N7 is protonated. AFM has shown that the title complex provokes DNA shrinkage. Preliminary biological tests have also been performed...
  7. pmc The geometry of DNA supercoils modulates the DNA cleavage activity of human topoisomerase I
    Amanda C Gentry
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Nucleic Acids Res 39:1014-22. 2011
    ....
  8. pmc The use of divalent metal ions by type II topoisomerases
    Joseph E Deweese
    Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, TN 37204 3951, USA
    Metallomics 2:450-9. 2010
    ..This article will focus primarily on eukaryotic type II topoisomerases and the roles of metal ions in the catalytic functions of these enzymes...
  9. pmc A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases
    Bryan H Schmidt
    Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA
    Nature 465:641-4. 2010
    ..This connection illustrates how an indispensable chromosome-disentangling machine auto-regulates DNA breakage to prevent the aberrant formation of mutagenic and cytotoxic genomic lesions...
  10. pmc Metnase promotes restart and repair of stalled and collapsed replication forks
    Leyma P De Haro
    Department of Molecular Genetics and Microbiology, Division of Hematology Oncology, Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
    Nucleic Acids Res 38:5681-91. 2010
    ..These results establish Metnase as a key factor that promotes restart of stalled replication forks, and implicate Metnase in the repair of collapsed forks...
  11. pmc Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II
    Rachael E Hawtin
    Sunesis Pharmaceuticals, Inc, South San Francisco, California, United States of America
    PLoS ONE 5:e10186. 2010
    ..This study defined voreloxin's anticancer mechanism of action as a critical component of rational clinical development informed by translational research...
  12. pmc Etoposide quinone is a redox-dependent topoisomerase II poison
    David A Jacob
    Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204 3951, USA
    Biochemistry 50:5660-7. 2011
    ..Our results support the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis...
  13. pmc Drug interactions with Bacillus anthracis topoisomerase IV: biochemical basis for quinolone action and resistance
    Katie J Aldred
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 51:370-81. 2012
    ..Our findings provide an underlying biochemical basis for the ability of quinazolinediones to overcome clinically relevant quinolone resistance mutations in bacterial type II topoisomerases...
  14. pmc Amsacrine as a topoisomerase II poison: importance of drug-DNA interactions
    Adam C Ketron
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Biochemistry 51:1730-9. 2012
    ....
  15. pmc Natural products as topoisomerase II poisons: effects of thymoquinone on DNA cleavage mediated by human topoisomerase IIα
    Rachel E Ashley
    Departments of Biochemistry and Medicine Hematology Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Chem Res Toxicol 27:787-93. 2014
    ..These findings indicate that thymoquinone can be added to the growing list of dietary and medicinal natural products with activity against human type II topoisomerases...
  16. pmc Topoisomerase II and leukemia
    Maryjean Pendleton
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
    Ann N Y Acad Sci 1310:98-110. 2014
    ..The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential. ..
  17. pmc Direct monitoring of the strand passage reaction of DNA topoisomerase II triggers checkpoint activation
    Katherine L Furniss
    Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, United States of America
    PLoS Genet 9:e1003832. 2013
    ..In contrast, we have described the first example of a distinct category of checkpoint mechanism that monitors the catalytic cycle of a single specific enzyme in order to determine when chromosome segregation can proceed faithfully. ..
  18. pmc Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions
    Katie J Aldred
    Departments of Biochemistry and Medicine Hematology Oncology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    ACS Chem Biol 8:2660-8. 2013
    ..anthracis topoisomerase IV but low activity against human topoisomerase IIα. ..
  19. pmc Epimerization of green tea catechins during brewing does not affect the ability to poison human type II topoisomerases
    M Anne Timmel
    Departments of Biochemistry and Medicine Hematology Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, United States
    Chem Res Toxicol 26:622-8. 2013
    ..Thus, the activity of covalent topoisomerase II poisons appears to be less sensitive to stereochemical changes than interfacial poisons...
  20. pmc Chiral discrimination and writhe-dependent relaxation mechanism of human topoisomerase IIα
    Yeonee Seol
    Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
    J Biol Chem 288:13695-703. 2013
    ..Human topoisomerase IIα unlinks catenated chromosomes and preferentially relaxes positive supercoils...
  21. pmc Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance
    Katie J Aldred
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Nucleic Acids Res 41:4628-39. 2013
    ....
  22. pmc Oxidative metabolites of curcumin poison human type II topoisomerases
    Adam C Ketron
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    Biochemistry 52:221-7. 2013
    ..Thus, even within the more complex spice formulation, oxidized curcumin intermediates appear to function as topoisomerase II poisons...
  23. pmc Structure of a topoisomerase II-DNA-nucleotide complex reveals a new control mechanism for ATPase activity
    Bryan H Schmidt
    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA
    Nat Struct Mol Biol 19:1147-54. 2012
    ..Our data indicate that the ATPase domains pivot about each other to ensure unidirectional strand passage and that this state senses bound DNA to promote ATP turnover and enzyme reset...
  24. pmc DNA cleavage and opening reactions of human topoisomerase IIα are regulated via Mg2+-mediated dynamic bending of gate-DNA
    Sanghwa Lee
    Department of Physics and Astronomy, Seoul National University, Seoul 151 747, Korea
    Proc Natl Acad Sci U S A 109:2925-30. 2012
    ..Our data strongly suggest that the accurate cleavage of DNA by topoisomerase II is regulated through a tight coordination with DNA bending...
  25. pmc Topoisomerase IIalpha binding domains of adenomatous polyposis coli influence cell cycle progression and aneuploidy
    Yang Wang
    Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA
    PLoS ONE 5:e9994. 2010
    ..Our previous investigation implicated the 15-amino acid repeat region of APC (M2-APC) in the regulation of the G2/M cell cycle transition through interaction with topoisomerase IIalpha (topo IIalpha)...
  26. pmc Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia
    Ashley N Mays
    Department of Medical and Molecular Genetics, King s College London School of Medicine, London, United Kingdom
    Blood 115:326-30. 2010
    ....
  27. pmc (-)-Epigallocatechin gallate, a major constituent of green tea, poisons human type II topoisomerases
    Omari J Bandele
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 21:936-43. 2008
    ..Taken together, these results provide strong evidence that EGCG is a redox-dependent topoisomerase II poison and utilizes a mechanism similar to that of 1,4-benzoquinone...
  28. pmc Tryptophane-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal
    Rikke From Frøhlich
    Department of Molecular Biology, Aarhus University, C F Møllers Allé Bldg 130, 8000 Arhus C, Denmark
    Nucleic Acids Res 35:6170-80. 2007
    ..33, 6621-6634] suggesting flexibility in distinct parts of the enzyme during clockwise or counterclockwise strand rotation...
  29. pmc DNA topoisomerase II, genotoxicity, and cancer
    A Kathleen McClendon
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Mutat Res 623:83-97. 2007
    ..This article discusses both aspects of human type II topoisomerases...
  30. pmc Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme
    Amy M Wilstermann
    Departments of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 46:8217-25. 2007
    ..The functional importance of E-ring substituents was confirmed by topoisomerase II-mediated DNA cleavage assays...
  31. pmc Mutation of cysteine residue 455 to alanine in human topoisomerase IIalpha confers hypersensitivity to quinones: enhancing DNA scission by closing the N-terminal protein gate
    Ryan P Bender
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 20:975-81. 2007
    ..These findings strongly support the hypothesis that the ability of quinones to block the N-terminal gate of the type II enzyme contributes to their actions as topoisomerase II poisons...
  32. pmc Bioflavonoids as poisons of human topoisomerase II alpha and II beta
    Omari J Bandele
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 46:6097-108. 2007
    ..These data support the hypothesis that bioflavonoids function as topoisomerase II poisons in humans and provide a framework for further analysis of these important dietary components...
  33. pmc Quinone-induced enhancement of DNA cleavage by human topoisomerase IIalpha: adduction of cysteine residues 392 and 405
    Ryan P Bender
    Departments of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 46:2856-64. 2007
    ..These findings indicate that adduction of Cys392 and Cys405 is important for the actions of quinones against the enzyme and increases levels of cleavage complexes primarily by inhibiting DNA religation...
  34. pmc Ability of viral topoisomerase II to discern the handedness of supercoiled DNA: bimodal recognition of DNA geometry by type II enzymes
    A Kathleen McClendon
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 45:11674-80. 2006
    ....
  35. ncbi Polychlorinated biphenyl quinone metabolites poison human topoisomerase IIalpha: altering enzyme function by blocking the N-terminal protein gate
    Ryan P Bender
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 45:10140-52. 2006
    ..This finding suggests that PCB quinones block the N-terminal gate by cross-linking the protomer subunits of topoisomerase IIalpha...
  36. ncbi Topoisomerase II and the etiology of chromosomal translocations
    Carolyn A Felix
    Division of Oncology, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    DNA Repair (Amst) 5:1093-108. 2006
    ..This review will summarize the evidence for topoisomerase II involvement in the genesis of translocations and extension of the model to acute leukemia in infants characterized by similar MLL translocations...
  37. pmc Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides
    Maria Duca
    UMR 5153, CNRS, Paris, France
    Nucleic Acids Res 34:1900-11. 2006
    ..Finally, drug-TFO conjugates are useful tools to investigate the mechanistic details of topo II poisoning...
  38. pmc Using 3'-bridging phosphorothiolates to isolate the forward DNA cleavage reaction of human topoisomerase IIalpha
    Joseph E Deweese
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 47:4129-40. 2008
    ..Phosphorothiolate substrates provide significant advantages over traditional "suicide substrates" and should be valuable for future studies on DNA scission and the topoisomerase II-DNA cleavage complex...
  39. pmc Substituents on etoposide that interact with human topoisomerase IIalpha in the binary enzyme-drug complex: contributions to etoposide binding and activity
    Ryan P Bender
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 47:4501-9. 2008
    ..The identification of etoposide substituents that contact topoisomerase IIalpha in the binary complex has predictive value for drug behavior in the enzyme-etoposide-DNA complex...
  40. pmc Dietary polyphenols as topoisomerase II poisons: B ring and C ring substituents determine the mechanism of enzyme-mediated DNA cleavage enhancement
    Omari J Bandele
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 21:1253-60. 2008
    ..Disruption of these elements abrogates enzyme binding and precludes the ability to function as a traditional topoisomerase II poison...
  41. pmc Cleavage of plasmid DNA by eukaryotic topoisomerase II
    Omari J Bandele
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
    Methods Mol Biol 582:39-47. 2009
    ..The assay is simple, straightforward, and does not require the use of radiolabeled substrates...
  42. pmc Metal ion interactions in the DNA cleavage/ligation active site of human topoisomerase IIalpha
    Joseph E Deweese
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 48:8940-7. 2009
    ..Furthermore, we propose that M(1)(2+) interacts with E461, D543, and D545 and M(2)(2+) interacts with E461 and D541...
  43. pmc Use of divalent metal ions in the dna cleavage reaction of human type II topoisomerases
    Joseph E Deweese
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 48:1862-9. 2009
    ..This last aspect of the model highlights a difference in metal ion utilization during DNA cleavage mediated by human topoisomerase IIalpha and IIbeta...
  44. pmc Coordinating the two protomer active sites of human topoisomerase IIalpha: nicks as topoisomerase II poisons
    Joseph E Deweese
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 48:1439-41. 2009
    ..Finally, the presence of a nick on one strand induces cleavage on the opposite strand. Thus, nicks are topoisomerase II poisons that generate novel sites of DNA cleavage...
  45. pmc Bimodal recognition of DNA geometry by human topoisomerase II alpha: preferential relaxation of positively supercoiled DNA requires elements in the C-terminal domain
    A Kathleen McClendon
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 47:13169-78. 2008
    ....
  46. pmc The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing
    Joseph E Deweese
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 0146 USA
    Nucleic Acids Res 37:738-48. 2009
    ..Finally, it will describe dietary and environmental agents that enhance DNA cleavage mediated by the enzyme...
  47. pmc The efficacy of topoisomerase II-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells
    Omari J Bandele
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 47:11900-8. 2008
    ..Taken together, these findings suggest that it may be possible to preferentially target topoisomerase IIalpha with etoposide by employing a schedule that utilizes pulsed drug treatment-recovery cycles...
  48. pmc Human topoisomerase IIalpha uses a two-metal-ion mechanism for DNA cleavage
    Joseph E Deweese
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Nucleic Acids Res 36:4883-93. 2008
    ..This interaction greatly accelerates rates of enzyme-mediated DNA cleavage, and most likely is needed to stabilize the leaving 3'-oxygen...
  49. pmc Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis
    Syed Khizer Hasan
    Department of Biopathology, University of Tor Vergata, Rome, Italy
    Blood 112:3383-90. 2008
    ..This study further supports the presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes that may underlie the propensity to develop this subtype of leukemia after exposure to this agent...
  50. pmc Interaction between tumor suppressor adenomatous polyposis coli and topoisomerase IIalpha: implication for the G2/M transition
    Yang Wang
    Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
    Mol Biol Cell 19:4076-85. 2008
    ..Finally, purified recombinant M2-APC enhanced topo IIalpha activity in vitro. Together, these data support a novel role for APC in the G2/M transition, potentially through association with topo IIalpha...
  51. pmc The geometry of DNA supercoils modulates topoisomerase-mediated DNA cleavage and enzyme response to anticancer drugs
    A Kathleen McClendon
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 45:3040-50. 2006
    ....

Research Grants30

  1. CONTROL OF DNA TOPOLOGY
    Yuk Ching Tse-Dinh; Fiscal Year: 2013
    ..coli and characterized biochemically. Success in these experiments would provide very useful information for discovery of novel antibacterial drugs targeting topoisomerase I specifically. ..
  2. New determinants of the DNA damage response in the fission yeast S. pombe
    MATTHEW J O'CONNELL; Fiscal Year: 2013
    ..Because these processes are ancient in origin, we use simple yeast cells to identify new genes that are relevant to human disease. Our proposal analyses three new genes in the response of cells to DNA damage. ..
  3. Polyploidy, aneuploidy and genome stability
    DAVID S PELLMAN; Fiscal Year: 2013
    ....
  4. Regulation of chromosome segregation by SMC complexes and Top2 in S. pombe
    MATTHEW J O'CONNELL; Fiscal Year: 2013
    ..This project studies proteins that are essential for accurate inheritance of chromosomes as cells divide. The public health relevance is thus central to the biology of cancer and aging. ..
  5. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  6. MLL in Hematopoiesis and Leukemia in the Zebrafish Model
    Carolyn A Felix; Fiscal Year: 2013
    ..The exploitation of zebrafish to model the functions of human MLL in the regulation of normal and malignant blood cell development will streamline future inroads to new molecularly targeted therapies for patients with MLL leukemia. ..
  7. ANTI-TOPOISOMERASE DRUG ACTION IN YEAST
    John L Nitiss; Fiscal Year: 2013
    ..The proposed studies will provide a detailed picture of how Top2 targeting drugs interact with the enzyme, and may lead to tools needed for designing safer and more effective drugs that target this enzyme. ..
  8. Spatial and Temporal Regulation of Angiogenesis
    HAROLD FISHER DVORAK; Fiscal Year: 2013
    ..abstract_text> ..
  9. Host-tumor cell interaction in myeloma: therapeutic applications
    Kenneth C Anderson; Fiscal Year: 2013
    ..Ultimately, our goal is to validate MM-host cell interactions as a target for novel therapeutics to improve patient outcome in MM. ..
  10. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  11. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  12. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..