Skip to Content

Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

 

Neil Osheroff, Ph.D.

John Coniglio Professor of Biochemistry
Professor of Medicine
Researcher

Contact Information:

Vanderbilt University Medical Center
654 Robinson Research Building
Nashville, TN 37232-0146
615-322-4338

Research Description

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
  • Wang Y, Azuma Y, Moore D, Osheroff N, Neufeld KL. Interaction between tumor suppressor adenomatous polyposis coli and topoisomerase IIalpha: implication for the G2/M transition. Mol. Biol. Cell [print-electronic]. 2008 Oct; 19(10): 4076-85. PMID: 18632987, PMCID: PMC2555924, PII: E07-12-1296, DOI: 10.1091/mbc.E07-12-1296, ISSN: 1939-4586.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18632987.
  • Deweese JE, Burgin AB, Osheroff N. Human topoisomerase IIalpha uses a two-metal-ion mechanism for DNA cleavage. Nucleic Acids Res [print-electronic]. 2008 Sep; 36(15): 4883-93. PMID: 18653531, PMCID: PMC2528187, PII: gkn466, DOI: 10.1093/nar/gkn466, ISSN: 1362-4962.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18653531.
  • Bender RP, Jablonksy MJ, Shadid M, Romaine I, Dunlap N, Anklin C, Graves DE, Osheroff N. Substituents on etoposide that interact with human topoisomerase IIalpha in the binary enzyme-drug complex: contributions to etoposide binding and activity. Biochemistry [print-electronic]. 2008 Apr 4/15/2008; 47(15): 4501-9. PMID: 18355043, PMCID: PMC2737519, DOI: 10.1021/bi702019z, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18355043.
  • Deweese JE, Burgin AB, Osheroff N. Using 3'-bridging phosphorothiolates to isolate the forward DNA cleavage reaction of human topoisomerase IIalpha. Biochemistry [print-electronic]. 2008 Apr 4/1/2008; 47(13): 4129-40. PMID: 18318502, PMCID: PMC2733888, DOI: 10.1021/bi702194x, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18318502.
  • Bandele OJ, Osheroff N. (-)-Epigallocatechin gallate, a major constituent of green tea, poisons human type II topoisomerases. Chem. Res. Toxicol [print-electronic]. 2008 Apr; 21(4): 936-43. PMID: 18293940, PMCID: PMC2893035, DOI: 10.1021/tx700434v, ISSN: 0893-228X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18293940.
  • Pilarski PP, Alan Johnstone D, Pettepher CC, Osheroff N. From music to macromolecules: using rich media/podcast lecture recordings to enhance the preclinical educational experience. Med Teach. 2008; 30(6): 630-2. PMID: 18677662, PII: 795456535, DOI: 10.1080/01421590802144302, ISSN: 1466-187X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18677662.
  • McClendon AK, Osheroff N. DNA topoisomerase II, genotoxicity, and cancer. Mutat. Res [print-electronic]. 2007 Oct 10/1/2007; 623(1-2): 83-97. PMID: 17681352, PMCID: PMC2679583, PII: S0027-5107(07)00266-7, DOI: 10.1016/j.mrfmmm.2007.06.009, ISSN: 0027-5107.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17681352.
  • Wilstermann AM, Bender RP, Godfrey M, Choi S, Anklin C, Berkowitz DB, Osheroff N, Graves DE. Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Biochemistry [print-electronic]. 2007 Jul 7/17/2007; 46(28): 8217-25. PMID: 17580961, PMCID: PMC2888091, DOI: 10.1021/bi700272u, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17580961.
  • Bender RP, Osheroff N. 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. Chem. Res. Toxicol [print-electronic]. 2007 Jun; 20(6): 975-81. PMID: 17516663, PMCID: PMC2893044, DOI: 10.1021/tx700062t, ISSN: 0893-228X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17516663.
  • Bandele OJ, Osheroff N. Bioflavonoids as poisons of human topoisomerase II alpha and II beta. Biochemistry [print-electronic]. 2007 May 5/22/2007; 46(20): 6097-108. PMID: 17458941, PMCID: PMC2893030, DOI: 10.1021/bi7000664, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17458941.
  • Bender RP, Ham AJ, Osheroff N. Quinone-induced enhancement of DNA cleavage by human topoisomerase IIalpha: adduction of cysteine residues 392 and 405. Biochemistry [print-electronic]. 2007 Mar 3/13/2007; 46(10): 2856-64. PMID: 17298034, PMCID: PMC2896225, DOI: 10.1021/bi062017l, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17298034.
  • Frøhlich RF, Veigaard C, Andersen FF, McClendon AK, Gentry AC, Andersen AH, Osheroff N, Stevnsner T, Knudsen BR. Tryptophane-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal. Nucleic Acids Res [print-electronic]. 2007; 35(18): 6170-80. PMID: 17827209, PMCID: PMC2094083, PII: gkm669, DOI: 10.1093/nar/gkm669, ISSN: 1362-4962.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17827209.
  • Osheroff N. Unraveling the structure of the variola topoisomerase IB-DNA complex: a possible new twist on smallpox therapy. Mol. Interv. 2006 Oct; 6(5): 245-8. PMID: 17035663, PII: 6/5/245, DOI: 10.1124/mi.6.5.4, ISSN: 1534-0384.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17035663.
  • McClendon AK, Dickey JS, Osheroff N. Ability of viral topoisomerase II to discern the handedness of supercoiled DNA: bimodal recognition of DNA geometry by type II enzymes. Biochemistry. 2006 Sep 9/26/2006; 45(38): 11674-80. PMID: 16981727, PMCID: PMC2517260, DOI: 10.1021/bi0520838, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16981727.
  • Felix CA, Kolaris CP, Osheroff N. Topoisomerase II and the etiology of chromosomal translocations. DNA Repair (Amst.) [print-electronic]. 2006 Sep 9/8/2006; 5(9-10): 1093-108. PMID: 16857431, PII: S1568-7864(06)00171-6, DOI: 10.1016/j.dnarep.2006.05.031, ISSN: 1568-7864.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16857431.
  • Bender RP, Lehmler HJ, Robertson LW, Ludewig G, Osheroff N. Polychlorinated biphenyl quinone metabolites poison human topoisomerase IIalpha: altering enzyme function by blocking the N-terminal protein gate. Biochemistry. 2006 Aug 8/22/2006; 45(33): 10140-52. PMID: 16906772, DOI: 10.1021/bi0524666, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16906772.
  • McClendon AK, Osheroff N. The geometry of DNA supercoils modulates topoisomerase-mediated DNA cleavage and enzyme response to anticancer drugs. Biochemistry. 2006 Mar 3/7/2006; 45(9): 3040-50. PMID: 16503659, PMCID: PMC2517258, DOI: 10.1021/bi051987q, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16503659.
  • Duca M, Guianvarc'h D, Oussedik K, Halby L, Garbesi A, Dauzonne D, Monneret C, Osheroff N, Giovannangeli C, Arimondo PB. Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides. Nucleic Acids Res [electronic-print]. 2006; 34(6): 1900-11. PMID: 16598074, PMCID: PMC1447649, PII: 34/6/1900, DOI: 10.1093/nar/gkl126, ISSN: 1362-4962.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16598074.
  • McClendon AK, Rodriguez AC, Osheroff N. Human topoisomerase IIalpha rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. J. Biol. Chem [print-electronic]. 2005 Nov 11/25/2005; 280(47): 39337-45. PMID: 16188892, PII: M503320200, DOI: 10.1074/jbc.M503320200, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16188892.
  • Dickey JS, Van Etten JL, Osheroff N. DNA methylation impacts the cleavage activity of Chlorella virus topoisomerase II. Biochemistry. 2005 Nov 11/22/2005; 44(46): 15378-86. PMID: 16285742, DOI: 10.1021/bi051334+, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16285742.
  • Dickey JS, Osheroff N. Impact of the C-terminal domain of topoisomerase IIalpha on the DNA cleavage activity of the human enzyme. Biochemistry. 2005 Aug 8/30/2005; 44(34): 11546-54. PMID: 16114891, PMCID: PMC2678941, DOI: 10.1021/bi050811l, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16114891.
  • Baldwin EL, Osheroff N. Etoposide, topoisomerase II and cancer. Curr Med Chem Anticancer Agents. 2005 Jul; 5(4): 363-72. PMID: 16101488, ISSN: 1568-0118.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/16101488.
  • Lindsey RH, Bender RP, Osheroff N. Stimulation of topoisomerase II-mediated DNA cleavage by benzene metabolites. Chem. Biol. Interact [print-electronic]. 2005 May 5/30/2005; 153-154: 197-205. PMID: 15935817, PII: S0009-2797(05)00086-4, DOI: 10.1016/j.cbi.2005.03.035, ISSN: 0009-2797.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15935817.
  • Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B, Parry A, Walz C, Wiemels JL, Segal MR, Adès L, Blair IA, Osheroff N, Peniket AJ, Lafage-Pochitaloff M, Cross NC, Chomienne C, Solomon E, Fenaux P, Grimwade D. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N. Engl. J. Med. 2005 Apr 4/14/2005; 352(15): 1529-38. PMID: 15829534, PII: 352/15/1529, DOI: 10.1056/NEJMoa042715, ISSN: 1533-4406.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15829534.
  • Lindsey RH, Bender RP, Osheroff N. Effects of benzene metabolites on DNA cleavage mediated by human topoisomerase II alpha: 1,4-hydroquinone is a topoisomerase II poison. Chem. Res. Toxicol. 2005 Apr; 18(4): 761-70. PMID: 15833037, DOI: 10.1021/tx049659z, ISSN: 0893-228X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15833037.
  • Dickey JS, Choi TJ, Van Etten JL, Osheroff N. Chlorella virus Marburg topoisomerase II: high DNA cleavage activity as a characteristic of Chlorella virus type II enzymes. Biochemistry. 2005 Mar 3/15/2005; 44(10): 3899-908. PMID: 15751965, DOI: 10.1021/bi047777f, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15751965.
  • Vélez-Cruz R, Riggins JN, Daniels JS, Cai H, Guengerich FP, Marnett LJ, Osheroff N. Exocyclic DNA lesions stimulate DNA cleavage mediated by human topoisomerase II alpha in vitro and in cultured cells. Biochemistry. 2005 Mar 3/15/2005; 44(10): 3972-81. PMID: 15751973, DOI: 10.1021/bi0478289, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15751973.
  • Baldwin EL, Berger AC, Corbett AH, Osheroff N. Mms22p protects Saccharomyces cerevisiae from DNA damage induced by topoisomerase II. Nucleic Acids Res [electronic-print]. 2005; 33(3): 1021-30. PMID: 15718301, PMCID: PMC549411, PII: 33/3/1021, DOI: 10.1093/nar/gki246, ISSN: 1362-4962.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15718301.
  • Bromberg KD, Vélez-Cruz R, Burgin AB, Osheroff N. DNA ligation catalyzed by human topoisomerase II alpha. Biochemistry. 2004 Oct 10/26/2004; 43(42): 13416-23. PMID: 15491148, DOI: 10.1021/bi049420h, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15491148.
  • Lindsey RH, Bromberg KD, Felix CA, Osheroff N. 1,4-Benzoquinone is a topoisomerase II poison. Biochemistry. 2004 Jun 6/15/2004; 43(23): 7563-74. PMID: 15182198, DOI: 10.1021/bi049756r, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15182198.
  • Bender RP, Lindsey RH, Burden DA, Osheroff N. N-acetyl-p-benzoquinone imine, the toxic metabolite of acetaminophen, is a topoisomerase II poison. Biochemistry. 2004 Mar 3/30/2004; 43(12): 3731-9. PMID: 15035644, DOI: 10.1021/bi036107r, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15035644.
  • Osheroff N. Diflomotecan. Ipsen. IDrugs. 2004 Mar; 7(3): 257-63. PMID: 15011101, ISSN: 1369-7056.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/15011101.
  • Baldwin EL, Byl JA, Osheroff N. Cobalt enhances DNA cleavage mediated by human topoisomerase II alpha in vitro and in cultured cells. Biochemistry. 2004 Jan 1/27/2004; 43(3): 728-35. PMID: 14730977, DOI: 10.1021/bi035472f, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/14730977.
  • Sappal DS, McClendon AK, Fleming JA, Thoroddsen V, Connolly K, Reimer C, Blackman RK, Bulawa CE, Osheroff N, Charlton P, Rudolph-Owen LA. Biological characterization of MLN944: a potent DNA binding agent. Mol. Cancer Ther. 2004 Jan; 3(1): 47-58. PMID: 14749475, ISSN: 1535-7163.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/14749475.
  • D.S. Sappal, A.K. McClendon, J.A. Fleming, V. Thoroddsen, K. Connolly, C. Reimer, R.K. Blackman, C.E. Bulawa, N. Osheroff, P. Charlton, and L.A. Rudolph-Owen. Biological Characterization of MLN944; A Potent DNA Binding Agent. Mol. Cancer. Ther. 2004; ((3)): 47-58.
  • R. Velez-Cruz, and N. Osheroff. Topoisomerases: Eukaryotic and Prokaryotic Type II. Encyclopedia of Molecular Biology (W. Lennarz, and M.D. Lane, eds.) Elsevier Science, San Diego, in press. 2004; 1: 806-11.
  • Whitmarsh RJ, Saginario C, Zhuo Y, Hilgenfeld E, Rappaport EF, Megonigal MD, Carroll M, Liu M, Osheroff N, Cheung NK, Slater DJ, Ried T, Knutsen T, Blair IA, Felix CA. Reciprocal DNA topoisomerase II cleavage events at 5'-TATTA-3' sequences in MLL and AF-9 create homologous single-stranded overhangs that anneal to form der(11) and der(9) genomic breakpoint junctions in treatment-related AML without further processing. Oncogene. 2003 Nov 11/20/2003; 22(52): 8448-59. PMID: 14627986, PII: 1207052, DOI: 10.1038/sj.onc.1207052, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/14627986.
  • Mårtensson S, Nygren J, Osheroff N, Hammarsten O. Activation of the DNA-dependent protein kinase by drug-induced and radiation-induced DNA strand breaks. Radiat. Res. 2003 Sep; 160(3): 291-301. PMID: 12926987, ISSN: 0033-7587.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12926987.
  • Sabourin M, Nitiss JL, Nitiss KC, Tatebayashi K, Ikeda H, Osheroff N. Yeast recombination pathways triggered by topoisomerase II-mediated DNA breaks. Nucleic Acids Res. 2003 Aug 8/1/2003; 31(15): 4373-84. PMID: 12888496, PMCID: PMC169887, ISSN: 1362-4962.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12888496.
  • Bromberg KD, Burgin AB, Osheroff N. Quinolone action against human topoisomerase IIalpha: stimulation of enzyme-mediated double-stranded DNA cleavage. Biochemistry. 2003 Apr 4/1/2003; 42(12): 3393-8. PMID: 12653542, DOI: 10.1021/bi027383t, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12653542.
  • Bromberg KD, Burgin AB, Osheroff N. A two-drug model for etoposide action against human topoisomerase IIalpha. J. Biol. Chem [print-electronic]. 2003 Feb 2/28/2003; 278(9): 7406-12. PMID: 12473657, PII: M212056200, DOI: 10.1074/jbc.M212056200, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12473657.
  • S. Martensson, J. Nygren, N. Osheroff, and O. Hammarsten. Activation of DNA-dependent PRotein Kinase by Drug and Radiation-induced DNA Strand Breaks. Radiation Res. 2003; ((160)): 291-301.
  • Wilstermann AM, Osheroff N. Stabilization of eukaryotic topoisomerase II-DNA cleavage complexes. Curr Top Med Chem. 2003; 3(3): 321-38. PMID: 12570766, ISSN: 1568-0266.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12570766.
  • Morrison C, Henzing AJ, Jensen ON, Osheroff N, Dodson H, Kandels-Lewis SE, Adams RR, Earnshaw WC. Proteomic analysis of human metaphase chromosomes reveals topoisomerase II alpha as an Aurora B substrate. Nucleic Acids Res. 2002 Dec 12/1/2002; 30(23): 5318-27. PMID: 12466558, PMCID: PMC137976, ISSN: 1362-4962.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12466558.
  • Fortune JM, Dickey JS, Lavrukhin OV, Van Etten JL, Lloyd RS, Osheroff N. Site-specific DNA cleavage by Chlorella virus topoisomerase II. Biochemistry. 2002 Oct 10/1/2002; 41(39): 11761-9. PMID: 12269818, PII: bi025802g, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12269818.
  • Bromberg KD, Hendricks C, Burgin AB, Osheroff N. Human topoisomerase IIalpha possesses an intrinsic nucleic acid specificity for DNA ligation. Use of 5' covalently activated oligonucleotide substrates to study enzyme mechanism. J. Biol. Chem [print-electronic]. 2002 Aug 8/23/2002; 277(34): 31201-6. PMID: 12050172, PII: M204741200, DOI: 10.1074/jbc.M204741200, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12050172.
  • Slater DJ, Hilgenfeld E, Rappaport EF, Shah N, Meek RG, Williams WR, Lovett BD, Osheroff N, Autar RS, Ried T, Felix CA. MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site. Oncogene. 2002 Jul 7/11/2002; 21(30): 4706-14. PMID: 12096348, DOI: 10.1038/sj.onc.1205572, ISSN: 0950-9232.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12096348.
  • Wilstermann AM, Osheroff N. Base excision repair intermediates as topoisomerase II poisons. J. Biol. Chem [print-electronic]. 2001 Dec 12/7/2001; 276(49): 46290-6. PMID: 11591703, PII: M105733200, DOI: 10.1074/jbc.M105733200, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11591703.
  • Lovett BD, Lo Nigro L, Rappaport EF, Blair IA, Osheroff N, Zheng N, Megonigal MD, Williams WR, Nowell PC, Felix CA. Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2001 Aug 8/14/2001; 98(17): 9802-7. PMID: 11493704, PMCID: PMC55533, PII: 171309898, DOI: 10.1073/pnas.171309898, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11493704.
  • Bromberg KD, Osheroff N. DNA cleavage and religation by human topoisomerase II alpha at high temperature. Biochemistry. 2001 Jul 7/27/2001; 40(28): 8410-8. PMID: 11444988, PII: bi010681q, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11444988.
  • Fortune JM, Lavrukhin OV, Gurnon JR, Van Etten JL, Lloyd RS, Osheroff N. Topoisomerase II from Chlorella virus PBCV-1 has an exceptionally high DNA cleavage activity. J. Biol. Chem [print-electronic]. 2001 Jun 6/29/2001; 276(26): 24401-8. PMID: 11323425, PII: M101693200, DOI: 10.1074/jbc.M101693200, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11323425.
  • Wilstermann AM, Osheroff N. Positioning the 3'-DNA terminus for topoisomerase II-mediated religation. J. Biol. Chem [print-electronic]. 2001 May 5/25/2001; 276(21): 17727-31. PMID: 11359787, PII: M100197200, DOI: 10.1074/jbc.M100197200, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11359787.
  • Anderson VE, Osheroff N. Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde. Curr. Pharm. Des. 2001 Mar; 7(5): 337-53. PMID: 11254893, ISSN: 1381-6128.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11254893.
  • Lovett BD, Strumberg D, Blair IA, Pang S, Burden DA, Megonigal MD, Rappaport EF, Rebbeck TR, Osheroff N, Pommier YG, Felix CA. Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints. Biochemistry. 2001 Feb 2/6/2001; 40(5): 1159-70. PMID: 11170441, PII: bi002361x, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11170441.
  • Byl JA, Cline SD, Utsugi T, Kobunai T, Yamada Y, Osheroff N. DNA topoisomerase II as the target for the anticancer drug TOP-53: mechanistic basis for drug action. Biochemistry. 2001 Jan 1/23/2001; 40(3): 712-8. PMID: 11170388, PII: bi0021838, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11170388.
  • Burden DA, Froelich-Ammon SJ, Osheroff N. Topoisomerase II-mediated cleavage of plasmid DNA. Methods Mol. Biol. 2001; 95: 283-9. PMID: 11089240, ISSN: 1064-3745.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11089240.
  • Fortune JM, Osheroff N. Topoisomerase II-catalyzed relaxation and catenation of plasmid DNA. Methods Mol. Biol. 2001; 95: 275-81. PMID: 11089239, ISSN: 1064-3745.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11089239.
  • J.A.W. Byl, T. Utsugi, T. Kobunai, Y. Yamada, and N. Osheroff. DNA Topoisomerase II as the Target for the Anticancer Drug TOP-53: Mechanistic Basis for Drug Action. Biochemistry. 2001; ((40)): 712-8.
  • Kingma PS, Fortune JM, Osheroff N. Topoisomerase II-catalyzed ATP hydrolysis as monitored by thin-layer chromatography. Methods Mol. Biol. 2001; 95: 51-6. PMID: 11089218, ISSN: 1064-3745.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/11089218.
  • V.E. Anderson, and N. Osheroff. Topoisomerase-Targeted Antibacterials: Turning Dr. Jekyll into Mr. Hyde. Curr. Pharm. Design. 2001; ((7)): 339-55.
  • Kluza J, Lansiaux A, Wattez N, Mahieu C, Osheroff N, Bailly C. Apoptotic response of HL-60 human leukemia cells to the antitumor drug TAS-103. Cancer Res. 2000 Aug 8/1/2000; 60(15): 4077-84. PMID: 10945613, ISSN: 0008-5472.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10945613.
  • Durrieu F, Samejima K, Fortune JM, Kandels-Lewis S, Osheroff N, Earnshaw WC. DNA topoisomerase IIalpha interacts with CAD nuclease and is involved in chromatin condensation during apoptotic execution. Curr. Biol. 2000 Jul 7/27/2000; 10(15): 923-6. PMID: 10959840, PII: S0960-9822(00)00620-5, ISSN: 0960-9822.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10959840.
  • Sabourin M, Osheroff N. Sensitivity of human type II topoisomerases to DNA damage: stimulation of enzyme-mediated DNA cleavage by abasic, oxidized and alkylated lesions. Nucleic Acids Res. 2000 May 5/1/2000; 28(9): 1947-54. PMID: 10756196, PMCID: PMC103304, PII: gkd320, ISSN: 1362-4962.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10756196.
  • Earnshaw WC, Samejima K, Durrieu F, Fortune J, Osheroff N. Biochemical mechanism of apoptotic execution. Ann. Endocrinol. (Paris). 2000 May; 61(2): 137. PMID: 10960326, PII: 59313, ISSN: 0003-4266.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10960326.
  • Bjergbaek L, Kingma P, Nielsen IS, Wang Y, Westergaard O, Osheroff N, Andersen AH. Communication between the ATPase and cleavage/religation domains of human topoisomerase IIalpha. J. Biol. Chem. 2000 Apr 4/28/2000; 275(17): 13041-8. PMID: 10777608, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10777608.
  • Anderson VE, Zaniewski RP, Kaczmarek FS, Gootz TD, Osheroff N. Action of quinolones against Staphylococcus aureus topoisomerase IV: basis for DNA cleavage enhancement. Biochemistry. 2000 Mar 3/14/2000; 39(10): 2726-32. PMID: 10704224, PII: bi992302n, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10704224.
  • Lavrukhin OV, Fortune JM, Wood TG, Burbank DE, Van Etten JL, Osheroff N, Lloyd RS. Topoisomerase II from Chlorella virus PBCV-1. Characterization of the smallest known type II topoisomerase. J. Biol. Chem. 2000 Mar 3/10/2000; 275(10): 6915-21. PMID: 10702252, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10702252.
  • Jensen LH, Nitiss KC, Rose A, Dong J, Zhou J, Hu T, Osheroff N, Jensen PB, Sehested M, Nitiss JL. A novel mechanism of cell killing by anti-topoisomerase II bisdioxopiperazines. J. Biol. Chem. 2000 Jan 1/21/2000; 275(3): 2137-46. PMID: 10636919, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10636919.
  • F. Durrieu, K. Samejima, J.M. Fortune, S. Kandels-Lewis, N. Osheroff, and W.C. Earnshaw. Involvement of DNA Topoisomerase II in Chromatin Condensation During Apoptotic Execution. Curr. Biol. (Brief Communication). 2000; ((10)): 923-6.
  • Fortune JM, Osheroff N. Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice. Prog. Nucleic Acid Res. Mol. Biol. 2000; 64: 221-53. PMID: 10697411, ISSN: 0079-6603.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10697411.
  • J.M. Fortune, and N. Osheroff. "Topoisomerase II as a Target for Anticancer Drugs: When Enzymes Stop Being Nice". Prog. Nuc. Acid Res. Mol Biol. 2000; 64: 221-53.
  • L. Bjergbæk, P. Kingma, I.S. Nielsen, Y. Wong, O. Westergaard, N. Osheroff, and A.H. Andersen. Uncoupling the ATPase and Cleavage/Ligation Activities of Human DNA Topoisomerase IIα by a Deletion in the N-terminal Region. J. Biol. Chem. 2000; ((275)): 13041-8.
  • L.H. Jensen, K.C. Nitiss, A. Rose, J. Dong, J. Zhou, T. Hu, N. Osheroff, P.B. Jensen, M. Sehested, and J.L. Nitiss. "A Novel Mechanism of Cell Killing by Anti-topoisomerase II Bisdioxopiperazines.". J. Biol. Chem. 2000; 275: 2137-46.
  • M. Sabourin, and N. Osheroff. Sensitivity of Human Type II Topoisomerases to DNA Damage: Stimulation of Enzyme-mediated DNA Cleavage by Abasic, Oxidized, and Alkylated Lesions. Nuc. Acids Res. 2000; ((28)): 1947-54.
  • O.V. Lavrukhin, J.M. Fortune, T.G. Wood, D.E. Burbank, J.L. Van Etten, N. Osheroff, and R.S. Lloyd. "Topoisomerase II from Chlorella Virus PBCV-1: Characterization of the Smallest Known Type II Topoisomerase.". J. Biol. Chem. 2000; 275: 6915-21.
  • V.E. Anderson, R.P. Zaniewski, F.S. Kaczmarek, T.D. Gootz, and N. Osheroff. "Action of Quinolones Against Staphylococcus aureus Topoisomerase IV: Basis for DNA Cleavage Enhancement". Biochemistry. 2000; 39: 2726-32.
  • Anderson VE, Zaniewski RP, Kaczmarek FS, Gootz TD, Osheroff N. Quinolones inhibit DNA religation mediated by Staphylococcus aureus topoisomerase IV. Changes in drug mechanism across evolutionary boundaries. J. Biol. Chem. 1999 Dec 12/10/1999; 274(50): 35927-32. PMID: 10585479, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10585479.
  • Byl JA, Fortune JM, Burden DA, Nitiss JL, Utsugi T, Yamada Y, Osheroff N. DNA topoisomerases as targets for the anticancer drug TAS-103: primary cellular target and DNA cleavage enhancement. Biochemistry. 1999 Nov 11/23/1999; 38(47): 15573-9. PMID: 10569941, PII: bi991791o, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10569941.
  • Cline SD, Jones WR, Stone MP, Osheroff N. DNA abasic lesions in a different light: solution structure of an endogenous topoisomerase II poison. Biochemistry. 1999 Nov 11/23/1999; 38(47): 15500-7. PMID: 10569932, PII: bi991750s, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10569932.
  • Fortune JM, Velea L, Graves DE, Utsugi T, Yamada Y, Osheroff N. DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition. Biochemistry. 1999 Nov 11/23/1999; 38(47): 15580-6. PMID: 10569942, PII: bi991792g, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10569942.
  • Cline SD, Osheroff N. Cytosine arabinoside lesions are position-specific topoisomerase II poisons and stimulate DNA cleavage mediated by the human type II enzymes. J. Biol. Chem. 1999 Oct 10/15/1999; 274(42): 29740-3. PMID: 10514448, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10514448.
  • Shapiro PS, Whalen AM, Tolwinski NS, Wilsbacher J, Froelich-Ammon SJ, Garcia M, Osheroff N, Ahn NG. Extracellular signal-regulated kinase activates topoisomerase IIalpha through a mechanism independent of phosphorylation. Mol. Cell. Biol. 1999 May; 19(5): 3551-60. PMID: 10207078, PMCID: PMC84147, ISSN: 0270-7306.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10207078.
  • Kingma PS, Burden DA, Osheroff N. Binding of etoposide to topoisomerase II in the absence of DNA: decreased affinity as a mechanism of drug resistance. Biochemistry. 1999 Mar 3/23/1999; 38(12): 3457-61. PMID: 10090731, PII: bi982855i, DOI: 10.1021/bi982855i, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/10090731.
  • Burden DA, Osheroff N. In vitro evolution of preferred topoisomerase II DNA cleavage sites. J. Biol. Chem. 1999 Feb 2/19/1999; 274(8): 5227-35. PMID: 9988773, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9988773.
  • Bjornsti MA, Osheroff N. Introduction to DNA topoisomerases. Methods Mol. Biol. 1999; 94: 1-8. PMID: 12844856, PII: 1-59259-259-7-1, DOI: 10.1385/1-59259-259-7:1, ISSN: 1064-3745.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12844856.
  • D.A. Burden, and N. Osheroff. "In Vitro Evolution of Preferred Topoisomerase II DNA Cleavage Sites.". J. Biol. Chem. 1999; 274: 5227-35.
  • Froelich-Ammon SJ, Kingma PS, Osheroff N. Purification of DNA topoisomerase II from Drosophila melanogaster. Methods Mol. Biol. 1999; 94: 199-212. PMID: 12844876, PII: 1-59259-259-7-199, DOI: 10.1385/1-59259-259-7:199, ISSN: 1064-3745.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/12844876.
  • J.A.W. Byl, J.M. Fortune, D.A. Burden, J.L. Nitiss, T. Utsugi, Y. Yamada, and N. Osheroff. "DNA Topoisomerases as Targets for the Anticancer Drug TAS-103: Primary Cellular Target and DNA Cleavage Enhancement.". Biochemistry. 1999; 38: 15573-9.
  • J.M. Fortune, L. Velea, D.E. Graves, T. Utsugi, Y. Yamada, and N. Osheroff. "DNA Topoisomerases as Targets for the Anticancer Drug TAS-103: DNA Interactions and Topoisomerase Catalytic Inhibition.". Biochemistry. 1999; 38: 15580-6.
  • P. Shapiro, A.M. Walen, N. Tolwinski, S.J. Froelich-Ammon, M. Garcia, N. Osheroff, and N.G. Ahn. "ERK Activates Topoisomerase II Alpha Through a Mechanism Independent of Phosphorylation.". Molec. Cell. Biol. 1999; 19: 3551-60.
  • P.S. Kingma, D.A. Burden, and N. Osheroff. "Binding of Etoposide to Topoisomerase II in the Absence of DNA: Decreased Affinity as a Mechanism of Drug Resistance.". Biochemistry. 1999; 38: 3457-61.
  • S.D. Cline, W.R. Jones, M.P. Stone, and N. Osheroff. "DNA Abasic Lesions in a Different Light: Structure of an Endogenous Topoisomerase II Poison.". Biochemistry. 1999; 38: 15500 15507.
  • S.D. Cline, and N. Osheroff. "Cytosine Arabinoside (AraC) Lesions are Position-Specific Topoisomerase II Poisons and Stimulate DNA Cleavage Mediated by the Human Type II Enzymes.". J. Biol. Chem. 1999; 274: 29740-3.
  • V.E. Anderson, R.P. Zaniewski, F.S. Kaczmarek, T.D. Gootz, and N. Osheroff. "Quinolones Inhibit DNA Religation Mediated by Staphylococcus aureus Topoisomerase IV: Changes in Drug Mechanism Across Evolutionary Boundaries.". J. Biol. Chem. 1999; 274: 35927-32.
  • Sabourin M, Byl JA, Hannah SE, Nitiss JL, Osheroff N. A mutant yeast topoisomerase II (top2G437S) with differential sensitivity to anticancer drugs in the presence and absence of ATP. J. Biol. Chem. 1998 Oct 10/30/1998; 273(44): 29086-92. PMID: 9786915, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9786915.
  • Burden DA, Osheroff N. Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim. Biophys. Acta. 1998 Oct 10/1/1998; 1400(1-3): 139-54. PMID: 9748545, PII: S0167-4781(98)00132-8, ISSN: 0006-3002.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9748545.
  • Kingma PS, Osheroff N. The response of eukaryotic topoisomerases to DNA damage. Biochim. Biophys. Acta. 1998 Oct 10/1/1998; 1400(1-3): 223-32. PMID: 9748592, PII: S0167-4781(98)00138-9, ISSN: 0006-3002.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9748592.
  • Osheroff N. DNA topoisomerases. Biochim. Biophys. Acta. 1998 Oct 10/1/1998; 1400(1-3): 1-2. PMID: 9867354, PII: S0167-4781(98)00123-7, ISSN: 0006-3002.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9867354.
  • Kingma PS, Osheroff N. Topoisomerase II-mediated DNA cleavage and religation in the absence of base pairing. Abasic lesions as a tool to dissect enzyme mechanism. J. Biol. Chem. 1998 Jul 7/17/1998; 273(29): 17999-8002. PMID: 9660751, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9660751.
  • Anderson VE, Gootz TD, Osheroff N. Topoisomerase IV catalysis and the mechanism of quinolone action. J. Biol. Chem. 1998 Jul 7/10/1998; 273(28): 17879-85. PMID: 9651393, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9651393.
  • Fortune JM, Osheroff N. Merbarone inhibits the catalytic activity of human topoisomerase IIalpha by blocking DNA cleavage. J. Biol. Chem. 1998 Jul 7/10/1998; 273(28): 17643-50. PMID: 9651360, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9651360.
  • Nitiss JL, Zhou J, Rose A, Hsiung Y, Gale KC, Osheroff N. The bis(naphthalimide) DMP-840 causes cytotoxicity by its action against eukaryotic topoisomerase II. Biochemistry. 1998 Mar 3/3/1998; 37(9): 3078-85. PMID: 9485461, PII: bi9723257, DOI: 10.1021/bi9723257, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9485461.
  • Marx G, Zhou H, Graves DE, Osheroff N. Covalent attachment of ethidium to DNA results in enhanced topoisomerase II-mediated DNA cleavage. Biochemistry. 1997 Dec 12/16/1997; 36(50): 15884-91. PMID: 9398321, PII: bi971858c, DOI: 10.1021/bi971858c, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9398321.
  • Cline SD, Macdonald TL, Osheroff N. Azatoxin is a mechanistic hybrid of the topoisomerase II-targeted anticancer drugs etoposide and ellipticine. Biochemistry. 1997 Oct 10/21/1997; 36(42): 13095-101. PMID: 9335572, PII: bi971770z, DOI: 10.1021/bi971770z, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9335572.
  • Kingma PS, Greider CA, Osheroff N. Spontaneous DNA lesions poison human topoisomerase IIalpha and stimulate cleavage proximal to leukemic 11q23 chromosomal breakpoints. Biochemistry. 1997 May 5/20/1997; 36(20): 5934-9. PMID: 9166762, PII: bi970507v, DOI: 10.1021/bi970507v, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9166762.
  • Kingma PS, Osheroff N. Spontaneous DNA damage stimulates topoisomerase II-mediated DNA cleavage. J. Biol. Chem. 1997 Mar 3/14/1997; 272(11): 7488-93. PMID: 9054451, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9054451.
  • Elsea SH, Westergaard M, Burden DA, Lomenick JP, Osheroff N. Quinolones share a common interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs. Biochemistry. 1997 Mar 3/11/1997; 36(10): 2919-24. PMID: 9062121, PII: bi962488f, DOI: 10.1021/bi962488f, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/9062121.
  • Kingma PS, Osheroff N. Apurinic sites are position-specific topoisomerase II poisons. J. Biol. Chem. 1997 Jan 1/10/1997; 272(2): 1148-55. PMID: 8995415, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8995415.
  • Burden DA, Kingma PS, Froelich-Ammon SJ, Bjornsti MA, Patchan MW, Thompson RB, Osheroff N. Topoisomerase II.etoposide interactions direct the formation of drug-induced enzyme-DNA cleavage complexes. J. Biol. Chem. 1996 Nov 11/15/1996; 271(46): 29238-44. PMID: 8910583, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8910583.
  • Froelich-Ammon SJ, Burden DA, Patchan MW, Elsea SH, Thompson RB, Osheroff N. Increased drug affinity as the mechanistic basis for drug hypersensitivity of a mutant type II topoisomerase. J. Biol. Chem. 1995 Nov 11/24/1995; 270(47): 28018-21. PMID: 7499285, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7499285.
  • Froelich-Ammon SJ, Osheroff N. Topoisomerase poisons: harnessing the dark side of enzyme mechanism. J. Biol. Chem. 1995 Sep 9/15/1995; 270(37): 21429-32. PMID: 7665550, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7665550.
  • Kingma PS, Corbett AH, Burcham PC, Marnett LJ, Osheroff N. Abasic sites stimulate double-stranded DNA cleavage mediated by topoisomerase II. DNA lesions as endogenous topoisomerase II poisons. J. Biol. Chem. 1995 Sep 9/15/1995; 270(37): 21441-4. PMID: 7665552, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7665552.
  • Hsiung Y, Elsea SH, Osheroff N, Nitiss JL. A mutation in yeast TOP2 homologous to a quinolone-resistant mutation in bacteria. Mutation of the amino acid homologous to Ser83 of Escherichia coli gyrA alters sensitivity to eukaryotic topoisomerase inhibitors. J. Biol. Chem. 1995 Sep 9/1/1995; 270(35): 20359-64. PMID: 7657608, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7657608.
  • Froelich-Ammon SJ, Patchan MW, Osheroff N, Thompson RB. Topoisomerase II binds to ellipticine in the absence or presence of DNA. Characterization of enzyme-drug interactions by fluorescence spectroscopy. J. Biol. Chem. 1995 Jun 6/23/1995; 270(25): 14998-5004. PMID: 7797481, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7797481.
  • Elsea SH, Hsiung Y, Nitiss JL, Osheroff N. A yeast type II topoisomerase selected for resistance to quinolones. Mutation of histidine 1012 to tyrosine confers resistance to nonintercalative drugs but hypersensitivity to ellipticine. J. Biol. Chem. 1995 Jan 1/27/1995; 270(4): 1913-20. PMID: 7829529, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7829529.
  • Lin LH, Van Eldik LJ, Osheroff N, Norden JJ. Inhibition of protein kinase C- and casein kinase II-mediated phosphorylation of GAP-43 by S100 beta. Brain Res. Mol. Brain Res. 1994 Sep; 25(3-4): 297-304. PMID: 7808229, ISSN: 0169-328X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/7808229.
  • Froelich-Ammon SJ, Gale KC, Osheroff N. Site-specific cleavage of a DNA hairpin by topoisomerase II. DNA secondary structure as a determinant of enzyme recognition/cleavage. J. Biol. Chem. 1994 Mar 3/11/1994; 269(10): 7719-25. PMID: 8125998, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8125998.
  • Osheroff N, Corbett AH, Elsea SH, Westergaard M. Defining functional drug-interaction domains on topoisomerase II by exploiting mechanistic differences between drug classes. Cancer Chemother. Pharmacol. 1994; 34 Suppl: S19-25. PMID: 8070023, ISSN: 0344-5704.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8070023.
  • Osheroff N, Corbett AH, Robinson MJ. Mechanism of action of topoisomerase II-targeted antineoplastic drugs. Adv. Pharmacol. 1994; 29B: 105-26. PMID: 8996604, ISSN: 1054-3589.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8996604.
  • Corbett AH, Guerry P, Pflieger P, Osheroff N. A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential. Antimicrob. Agents Chemother. 1993 Dec; 37(12): 2599-605. PMID: 8109923, PMCID: PMC192751, ISSN: 0066-4804.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8109923.
  • Elsea SH, McGuirk PR, Gootz TD, Moynihan M, Osheroff N. Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential. Antimicrob. Agents Chemother. 1993 Oct; 37(10): 2179-86. PMID: 8257142, PMCID: PMC192247, ISSN: 0066-4804.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8257142.
  • Corbett AH, Osheroff N. When good enzymes go bad: conversion of topoisomerase II to a cellular toxin by antineoplastic drugs. Chem. Res. Toxicol. 1993 Sep; 6(5): 585-97. PMID: 8292734, ISSN: 0893-228X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8292734.
  • Kroeger PE, Osheroff N, Rowe TC. Analysis of topoisomerase II-mediated DNA cleavage in the 5'-region of the Drosophila hsp70 gene. Identification of a novel half-site DNA substrate for topoisomerase II cleavage. J. Biol. Chem. 1993 Aug 8/5/1993; 268(22): 16449-57. PMID: 8393863, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8393863.
  • Corbett AH, Hong D, Osheroff N. Exploiting mechanistic differences between drug classes to define functional drug interaction domains on topoisomerase II. Evidence that several diverse DNA cleavage-enhancing agents share a common site of action on the enzyme. J. Biol. Chem. 1993 Jul 7/5/1993; 268(19): 14394-8. PMID: 8390992, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8390992.
  • Robinson MJ, Corbett AH, Osheroff N. Effects of topoisomerase II-targeted drugs on enzyme-mediated DNA cleavage and ATP hydrolysis: evidence for distinct drug interaction domains on topoisomerase II. Biochemistry. 1993 Apr 4/13/1993; 32(14): 3638-43. PMID: 8385484, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8385484.
  • Froelich-Ammon SJ, McGuirk PR, Gootz TD, Jefson MR, Osheroff N. Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme. Antimicrob. Agents Chemother. 1993 Apr; 37(4): 646-51. PMID: 8388196, PMCID: PMC187729, ISSN: 0066-4804.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8388196.
  • Corbett AH, Fernald AW, Osheroff N. Protein kinase C modulates the catalytic activity of topoisomerase II by enhancing the rate of ATP hydrolysis: evidence for a common mechanism of regulation by phosphorylation. Biochemistry. 1993 Mar 3/2/1993; 32(8): 2090-7. PMID: 8383533, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/8383533.
  • Corbett AH, DeVore RF, Osheroff N. Effect of casein kinase II-mediated phosphorylation on the catalytic cycle of topoisomerase II. Regulation of enzyme activity by enhancement of ATP hydrolysis. J. Biol. Chem. 1992 Oct 10/5/1992; 267(28): 20513-8. PMID: 1328202, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1328202.
  • Elsea SH, Osheroff N, Nitiss JL. Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast. J. Biol. Chem. 1992 Jul 7/5/1992; 267(19): 13150-3. PMID: 1320012, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1320012.
  • Gale KC, Osheroff N. Intrinsic intermolecular DNA ligation activity of eukaryotic topoisomerase II. Potential roles in recombination. J. Biol. Chem. 1992 Jun 6/15/1992; 267(17): 12090-7. PMID: 1318309, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1318309.
  • DeVore RF, Corbett AH, Osheroff N. Phosphorylation of topoisomerase II by casein kinase II and protein kinase C: effects on enzyme-mediated DNA cleavage/religation and sensitivity to the antineoplastic drugs etoposide and 4'-(9-acridinylamino)methane-sulfon-m-anisidide. Cancer Res. 1992 Apr 4/15/1992; 52(8): 2156-61. PMID: 1313738, ISSN: 0008-5472.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1313738.
  • Robinson MJ, Martin BA, Gootz TD, McGuirk PR, Osheroff N. Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group. Antimicrob. Agents Chemother. 1992 Apr; 36(4): 751-6. PMID: 1323952, PMCID: PMC189387, ISSN: 0066-4804.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1323952.
  • Corbett AH, Zechiedrich EL, Osheroff N. A role for the passage helix in the DNA cleavage reaction of eukaryotic topoisomerase II. A two-site model for enzyme-mediated DNA cleavage. J. Biol. Chem. 1992 Jan 1/15/1992; 267(2): 683-6. PMID: 1309770, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1309770.
  • Corbett AH, Zechiedrich EL, Lloyd RS, Osheroff N. Inhibition of eukaryotic topoisomerase II by ultraviolet-induced cyclobutane pyrimidine dimers. J. Biol. Chem. 1991 Oct 10/15/1991; 266(29): 19666-71. PMID: 1655791, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1655791.
  • Robinson MJ, Martin BA, Gootz TD, McGuirk PR, Moynihan M, Sutcliffe JA, Osheroff N. Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage. J. Biol. Chem. 1991 Aug 8/5/1991; 266(22): 14585-92. PMID: 1650363, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1650363.
  • Osheroff N, Zechiedrich EL, Gale KC. Catalytic function of DNA topoisomerase II. Bioessays. 1991 Jun; 13(6): 269-73. PMID: 1654050, DOI: 10.1002/bies.950130603, ISSN: 0265-9247.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1654050.
  • Robinson MJ, Osheroff N. Effects of antineoplastic drugs on the post-strand-passage DNA cleavage/religation equilibrium of topoisomerase II. Biochemistry. 1991 Feb 2/19/1991; 30(7): 1807-13. PMID: 1847075, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/1847075.
  • Zechiedrich EL, Osheroff N. Eukaryotic topoisomerases recognize nucleic acid topology by preferentially interacting with DNA crossovers. EMBO J. 1990 Dec; 9(13): 4555-62. PMID: 2176156, PMCID: PMC552253, ISSN: 0261-4189.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2176156.
  • Gale KC, Osheroff N. Uncoupling the DNA cleavage and religation activities of topoisomerase II with a single-stranded nucleic acid substrate: evidence for an active enzyme-cleaved DNA intermediate. Biochemistry. 1990 Oct 10/16/1990; 29(41): 9538-45. PMID: 2176849, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2176849.
  • Robinson MJ, Osheroff N. Stabilization of the topoisomerase II-DNA cleavage complex by antineoplastic drugs: inhibition of enzyme-mediated DNA religation by 4'-(9-acridinylamino)methanesulfon-m-anisidide. Biochemistry. 1990 Mar 3/13/1990; 29(10): 2511-5. PMID: 2159323, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2159323.
  • Ackerman P, Glover CV, Osheroff N. Stimulation of casein kinase II by epidermal growth factor: relationship between the physiological activity of the kinase and the phosphorylation state of its beta subunit. Proc. Natl. Acad. Sci. U.S.A. 1990 Jan; 87(2): 821-5. PMID: 2300566, PMCID: PMC53358, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2300566.
  • Andersen AH, Christiansen K, Zechiedrich EL, Jensen PS, Osheroff N, Westergaard O. Strand specificity of the topoisomerase II mediated double-stranded DNA cleavage reaction. Biochemistry. 1989 Jul 7/25/1989; 28(15): 6237-44. PMID: 2551368, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2551368.
  • Osheroff N. Effect of antineoplastic agents on the DNA cleavage/religation reaction of eukaryotic topoisomerase II: inhibition of DNA religation by etoposide. Biochemistry. 1989 Jul 7/25/1989; 28(15): 6157-60. PMID: 2551366, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2551366.
  • Zechiedrich EL, Christiansen K, Andersen AH, Westergaard O, Osheroff N. Double-stranded DNA cleavage/religation reaction of eukaryotic topoisomerase II: evidence for a nicked DNA intermediate. Biochemistry. 1989 Jul 7/25/1989; 28(15): 6229-36. PMID: 2551367, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2551367.
  • Ackerman P, Osheroff N. Regulation of casein kinase II activity by epidermal growth factor in human A-431 carcinoma cells. J. Biol. Chem. 1989 Jul 7/15/1989; 264(20): 11958-65. PMID: 2473067, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2473067.
  • Osheroff N. Biochemical basis for the interactions of type I and type II topoisomerases with DNA. Pharmacol. Ther. 1989; 41(1-2): 223-41. PMID: 2540496, PII: 0163-7258(89)90108-3, ISSN: 0163-7258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2540496.
  • Ackerman P, Glover CV, Osheroff N. Phosphorylation of DNA topoisomerase II in vivo and in total homogenates of Drosophila Kc cells. The role of casein kinase II. J. Biol. Chem. 1988 Sep 9/5/1988; 263(25): 12653-60. PMID: 2842338, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2842338.
  • Osheroff N. Role of the divalent cation in topoisomerase II mediated reactions. Biochemistry. 1987 Oct 10/6/1987; 26(20): 6402-6. PMID: 2827726, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2827726.
  • Osheroff N, Zechiedrich EL. Calcium-promoted DNA cleavage by eukaryotic topoisomerase II: trapping the covalent enzyme-DNA complex in an active form. Biochemistry. 1987 Jul 7/14/1987; 26(14): 4303-9. PMID: 2822084, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2822084.
  • Armstrong GD, Chapman SK, Sisley MJ, Sykes AG, Aitken A, Osheroff N, Margoliash E. Preferred sites on cytochrome c for electron transfer with two positively charged blue copper proteins, Anabaena variabilis plastocyanin and stellacyanin. Biochemistry. 1986 Nov 11/4/1986; 25(22): 6947-51. PMID: 3026438, ISSN: 0006-2960.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/3026438.
  • Osheroff N. Eukaryotic topoisomerase II. Characterization of enzyme turnover. J. Biol. Chem. 1986 Jul 7/25/1986; 261(21): 9944-50. PMID: 3015913, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/3015913.
  • Guyer CA, Morgan DG, Osheroff N, Staros JV. Purification and characterization of a periplasmic oligopeptide binding protein from Escherichia coli. J. Biol. Chem. 1985 Sep 9/5/1985; 260(19): 10812-8. PMID: 3897225, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/3897225.
  • Berrios M, Osheroff N, Fisher PA. In situ localization of DNA topoisomerase II, a major polypeptide component of the Drosophila nuclear matrix fraction. Proc. Natl. Acad. Sci. U.S.A. 1985 Jun; 82(12): 4142-6. PMID: 2987966, PMCID: PMC397951, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2987966.
  • Ackerman P, Glover CV, Osheroff N. Phosphorylation of DNA topoisomerase II by casein kinase II: modulation of eukaryotic topoisomerase II activity in vitro. Proc. Natl. Acad. Sci. U.S.A. 1985 May; 82(10): 3164-8. PMID: 2987912, PMCID: PMC397735, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/2987912.
  • Osheroff N, Shelton ER, Brutlag DL. DNA topoisomerase II from Drosophila melanogaster. Relaxation of supercoiled DNA. J. Biol. Chem. 1983 Aug 8/10/1983; 258(15): 9536-43. PMID: 6308011, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6308011.
  • Shelton ER, Osheroff N, Brutlag DL. DNA topoisomerase II from Drosophila melanogaster. Purification and physical characterization. J. Biol. Chem. 1983 Aug 8/10/1983; 258(15): 9530-5. PMID: 6308010, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6308010.
  • Butler J, Chapman SK, Davies DM, Sykes AG, Speck SH, Osheroff N, Margoliash E. Preferred sites for electron transfer between cytochrome c and iron and cobalt complexes. J. Biol. Chem. 1983 May 5/25/1983; 258(10): 6400-4. PMID: 6304037, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6304037.
  • Osheroff N, Speck SH, Margoliash E, Veerman EC, Wilms J, König BW, Muijsers AO. The reaction of primate cytochromes c with cytochrome c oxidase. Analysis of the polarographic assay. J. Biol. Chem. 1983 May 5/10/1983; 258(9): 5731-8. PMID: 6304097, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6304097.
  • Veerman EC, Wilms J, Dekker HL, Muijsers AO, van Buuren KJ, van Gelder BF, Osheroff N, Speck SH, Margoliash E. The presteady state reaction of chemically modified cytochromes c with cytochrome oxidase. J. Biol. Chem. 1983 May 5/10/1983; 258(9): 5739-45. PMID: 6304098, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6304098.
  • Speck SH, Koppenol WH, Dethmers JK, Osheroff N, Margoliash E, Rajagopalan KV. Definition of cytochrome c binding domains by chemical modification. Interaction of horse cytochrome c with beef sulfite oxidase and analysis of steady state kinetics. J. Biol. Chem. 1981 Jul 7/25/1981; 256(14): 7394-400. PMID: 6265448, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6265448.
  • Osheroff N, Brautigan DL, Margoliash E. Definition of enzymic interaction domains on cytochrome c. Purification and activity of singly substituted carboxydinitrophenyl-lysine 7, 25, 73, 86, and 99 cytochromes c. J. Biol. Chem. 1980 Sep 9/10/1980; 255(17): 8245-51. PMID: 6251050, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6251050.
  • Osheroff N, Brautigan DL, Margoliash E. Mapping of anion binding sites on cytochrome c by differential chemical modification of lysine residues. Proc. Natl. Acad. Sci. U.S.A. 1980 Aug; 77(8): 4439-43. PMID: 6254024, PMCID: PMC349859, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6254024.
  • König BW, Osheroff N, Wilms J, Muijsers AO, Dekker HL, Margoliash E. Mapping of the interaction domain for purified cytochrome c1 on cytochrome c. FEBS Lett. 1980 Mar 3/10/1980; 111(2): 395-8. PMID: 6244193, PII: 0014-5793(80)80835-0, ISSN: 0014-5793.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6244193.
  • Osheroff N, Borden D, Koppenol WH, Margoliash E. Electrostatic interactions in cytochrome c. The role of interactions between residues 13 and 90 and residues 79 and 47 in stabilizing the heme crevice structure. J. Biol. Chem. 1980 Feb 2/25/1980; 255(4): 1689-97. PMID: 6243646, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/6243646.
  • Osheroff N, Jemmerson R, Speck SH, Ferguson-Miller S, Margoliash E. Site-specific anti-cytochrome c antibodies. Inhibition of the reactions between cytochrome c and its respiratory chain electron exchange partners. J. Biol. Chem. 1979 Dec 12/25/1979; 254(24): 12717-24. PMID: 91615, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/91615.
  • Speck SH, Ferguson-Miller S, Osheroff N, Margoliash E. Definition of cytochrome c binding domains by chemical modification: kinetics of reaction with beef mitochondrial reductase and functional organization of the respiratory chain. Proc. Natl. Acad. Sci. U.S.A. 1979 Jan; 76(1): 155-9. PMID: 218193, PMCID: PMC382895, ISSN: 0027-8424.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/218193.
  • Kang CH, Brautigan DL, Osheroff N, Margoliash E. Definitaion of cytochrome c binding domains by chemical modification. Reaction of carboxydinitrophenyl- and trinitrophenyl-cytochromes c with baker's yeast cytochrome c peroxidase. J. Biol. Chem. 1978 Sep 9/25/1978; 253(18): 6502-10. PMID: 210187, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/210187.
  • Osheroff N, Feinberg BA, Margoliash E, Morrison M. Lactoperoxidase-catalyzed iodination of horse cytochrome c:monoiodotyrosyl 74 cytochrome c. J. Biol. Chem. 1977 Nov 11/10/1977; 252(21): 7743-51. PMID: 199598, ISSN: 0021-9258.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/199598.