type i dna topoisomerases

Summary

Summary: DNA TOPOISOMERASES that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. DNA Topoisomerases, Type I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.

Top Publications

  1. pmc The mechanism of topoisomerase I poisoning by a camptothecin analog
    Bart L Staker
    deCODE Genetics, Incorporated, BioStructures Group, 7869 Northeast Day Road West, Bainbridge Island, WA 98110, USA
    Proc Natl Acad Sci U S A 99:15387-92. 2002
  2. ncbi Topoisomerase I inhibitors: camptothecins and beyond
    Yves Pommier
    Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892 4255, USA
    Nat Rev Cancer 6:789-802. 2006
  3. ncbi Origin and evolution of DNA topoisomerases
    Patrick Forterre
    Institut de Genetique et Microbiologie, UMR8621, Universite Paris Sud 11, Bat 400 409, 91405 Orsay Cedex, France
    Biochimie 89:427-46. 2007
  4. ncbi DNA topoisomerases: structure, function, and mechanism
    J J Champoux
    Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195 7242, USA
    Annu Rev Biochem 70:369-413. 2001
  5. ncbi Cellular roles of DNA topoisomerases: a molecular perspective
    James C Wang
    Department of Molecular and Cellular Biology, Harvard University, Fairchild Building, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA
    Nat Rev Mol Cell Biol 3:430-40. 2002
  6. pmc RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability
    Dongyi Xu
    Laboratory of Genetics, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, Baltimore, Maryland 21224, USA
    Genes Dev 22:2843-55. 2008
  7. pmc DNA bending, compaction and negative supercoiling by the architectural protein Sso7d of Sulfolobus solfataricus
    Alessandra Napoli
    Institute of Protein Biochemistry and Enzymology, Consiglio Nazionale delle Ricerche, Via Pietro Castellino 111, 80131 Naples, Italy
    Nucleic Acids Res 30:2656-62. 2002
  8. pmc BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome
    Thiyam Ramsing Singh
    Division of Experimental Hematology and Cancer Biology, Cincinnati Children s Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
    Genes Dev 22:2856-68. 2008
  9. ncbi Antitumour drugs impede DNA uncoiling by topoisomerase I
    Daniel A Koster
    Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
    Nature 448:213-7. 2007
  10. ncbi Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast
    Grzegorz Ira
    Rosenstiel Center and Department of Biology, Brandeis University, Waltham, MA 02454, USA
    Cell 115:401-11. 2003

Detail Information

Publications333 found, 100 shown here

  1. pmc The mechanism of topoisomerase I poisoning by a camptothecin analog
    Bart L Staker
    deCODE Genetics, Incorporated, BioStructures Group, 7869 Northeast Day Road West, Bainbridge Island, WA 98110, USA
    Proc Natl Acad Sci U S A 99:15387-92. 2002
    ..The first class includes changes to residues that contribute to direct interactions with the drug, whereas a second class would alter interactions with the DNA and thereby destabilize the drug-binding site...
  2. ncbi Topoisomerase I inhibitors: camptothecins and beyond
    Yves Pommier
    Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892 4255, USA
    Nat Rev Cancer 6:789-802. 2006
    ....
  3. ncbi Origin and evolution of DNA topoisomerases
    Patrick Forterre
    Institut de Genetique et Microbiologie, UMR8621, Universite Paris Sud 11, Bat 400 409, 91405 Orsay Cedex, France
    Biochimie 89:427-46. 2007
    ....
  4. ncbi DNA topoisomerases: structure, function, and mechanism
    J J Champoux
    Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195 7242, USA
    Annu Rev Biochem 70:369-413. 2001
    ..For the type II topoisomerases, the binding and hydrolysis of ATP further modulate conformational changes in the enzymes to effect changes in DNA topology...
  5. ncbi Cellular roles of DNA topoisomerases: a molecular perspective
    James C Wang
    Department of Molecular and Cellular Biology, Harvard University, Fairchild Building, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA
    Nat Rev Mol Cell Biol 3:430-40. 2002
    ..In this review, the cellular roles of these enzymes are examined from a molecular point of view...
  6. pmc RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability
    Dongyi Xu
    Laboratory of Genetics, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, Baltimore, Maryland 21224, USA
    Genes Dev 22:2843-55. 2008
    ..Our data suggest that multi-OB-fold complexes mediate two modes of BLM action: via RPA-mediated protein-DNA interaction, and via RMI-mediated protein-protein interactions...
  7. pmc DNA bending, compaction and negative supercoiling by the architectural protein Sso7d of Sulfolobus solfataricus
    Alessandra Napoli
    Institute of Protein Biochemistry and Enzymology, Consiglio Nazionale delle Ricerche, Via Pietro Castellino 111, 80131 Naples, Italy
    Nucleic Acids Res 30:2656-62. 2002
    ..The proposed biological relevance of these observations is that these proteins might model the behaviour of DNA in constrained chromatin environments...
  8. pmc BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome
    Thiyam Ramsing Singh
    Division of Experimental Hematology and Cancer Biology, Cincinnati Children s Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
    Genes Dev 22:2856-68. 2008
    ..Finally, BLAP18/RMI2 stimulates the dHJ resolution capability of the BTB complex. Together, these results establish BLAP18/RMI2 as an essential member of the BTB dHJ dissolvasome that is required for the maintenance of a stable genome...
  9. ncbi Antitumour drugs impede DNA uncoiling by topoisomerase I
    Daniel A Koster
    Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
    Nature 448:213-7. 2007
    ..This combination of single-molecule and in vivo data suggests a cytotoxic mechanism for camptothecins, in which the accumulation of positive supercoils ahead of the replication machinery induces potentially lethal DNA lesions...
  10. ncbi Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast
    Grzegorz Ira
    Rosenstiel Center and Department of Biology, Brandeis University, Waltham, MA 02454, USA
    Cell 115:401-11. 2003
    ..Srs2 promotes the noncrossover synthesis-dependent strand-annealing (SDSA) pathway, apparently by regulating Rad51 binding during strand exchange...
  11. ncbi Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells
    F B Johnson
    Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA
    Cancer Res 60:1162-7. 2000
    ..Thus, mechanisms by which RecQ helicases and topoisomerase III proteins cooperate to maintain genomic stability in model organisms likely apply to humans...
  12. ncbi Reconstitution of enzymatic activity by the association of the cap and catalytic domains of human topoisomerase I
    Zheng Yang
    Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 98195 7242, USA
    J Biol Chem 277:30815-23. 2002
    ..These results suggest that activation of the catalytic domain of the enzyme for cleavage requires both DNA binding and the presence of the cap region of the protein...
  13. pmc SCT1 mutants suppress the camptothecin sensitivity of yeast cells expressing wild-type DNA topoisomerase I
    E A Kauh
    Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Proc Natl Acad Sci U S A 92:6299-303. 1995
    ..SCT1 cell sensitivity to other DNA-damaging agents suggests that alterations in SCT1 function suppress camptothecin-induced DNA damage produced in the presence of yeast DNA topoisomerase I...
  14. ncbi Holliday junction processing activity of the BLM-Topo IIIalpha-BLAP75 complex
    Wendy Bussen
    Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Biol Chem 282:31484-92. 2007
    ....
  15. ncbi Reverse gyrase recruitment to DNA after UV light irradiation in Sulfolobus solfataricus
    Alessandra Napoli
    Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Via P Castellino 111, 80131 Naples, Italy
    J Biol Chem 279:33192-8. 2004
    ..Our results suggest a general role of the association of such activities in maintaining genome integrity and a mutual effect of DNA topology and repair...
  16. ncbi Mechanism of action of camptothecin
    L F Liu
    Department of Pharmacology, UMDNJ Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
    Ann N Y Acad Sci 922:1-10. 2000
    ..The second involves SUMO conjugation to topo-I. The potentials roles of these new mechanisms for repair of topo-I-mediated DNA damage in determining CPT sensitivity/resistance in tumor cells are discussed...
  17. pmc A two-subunit type I DNA topoisomerase (reverse gyrase) from an extreme hyperthermophile
    R Krah
    Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Proc Natl Acad Sci U S A 93:106-10. 1996
    ..The appearance of this unique structure in a highly conserved enzyme family supports the hypothesis that the methanogens branched from other prokaryotes and eukaryotes very early in evolution...
  18. ncbi p53 disruption profoundly alters the response of human glioblastoma cells to DNA topoisomerase I inhibition
    Yinglin Wang
    Department of Pathology and Laboratory Medicine, UCLA School of Medicine, 13 317 Center for the Health Science, Los Angeles, CA 90095 1732, USA
    Oncogene 23:1283-90. 2004
    ..These results indicate that p53 disruption has a dramatic effect on how glioblastoma cells process topoisomerase I inhibitor-mediated DNA damage...
  19. ncbi Directed evolution to increase camptothecin sensitivity of human DNA topoisomerase I
    S Scaldaferro
    Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy
    Chem Biol 8:871-81. 2001
    ..Such drug-hypersensitive topoisomerases may be useful in developing DNA cutters with high cell lethality and in new drug discovery programs...
  20. ncbi Nonclassic functions of human topoisomerase I: genome-wide and pharmacologic analyses
    Ze Hong Miao
    Laboratories of Molecular Pharmacology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
    Cancer Res 67:8752-61. 2007
    ..The reported cell lines and approaches described in this article provide new tools to perform detailed functional analyses related to Top1 function...
  21. ncbi The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons
    Karen Flatten
    Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
    J Biol Chem 280:14349-55. 2005
    ..Collectively, these results show that the ATR/Chk1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells and identify a potential approach for enhancing the efficacy of these drugs...
  22. pmc Transcriptional consequences of topoisomerase inhibition
    I Collins
    Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1500, USA
    Mol Cell Biol 21:8437-51. 2001
    ..The results have ramifications for the use of these drugs as antineoplastic agents...
  23. pmc TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo
    Sachin Katyal
    Department Genetics and Tumor Cell Biology, St Jude Children s Research Hospital, Memphis, TN 38105, USA
    EMBO J 26:4720-31. 2007
    ..These data indicate that TDP1 is required for neural homeostasis, and reveal a widespread requisite for TDP1 function in response to acutely elevated levels of Top1-associated DNA strand breaks...
  24. pmc Evidence of the crucial role of the linker domain on the catalytic activity of human topoisomerase I by experimental and simulative characterization of the Lys681Ala mutant
    Paola Fiorani
    Department of Biology, University of Rome Tor Vergata, CNR National Research Council, INFM National Institute for the Physics of Matter, Rome 00133, Italy
    Nucleic Acids Res 37:6849-58. 2009
    ..Taken together these results indicate the existence of a long range communication between the linker domain and the active site region and points out the crucial role of the linker in the modulation of the catalytic activity...
  25. ncbi Single mutation in the linker domain confers protein flexibility and camptothecin resistance to human topoisomerase I
    Paola Fiorani
    Department of Biology, University of Padua, Via U Bassi 58 B, Padua 35131, Italy
    J Biol Chem 278:43268-75. 2003
    ..The increase in religation rate of the mutant, explained by means of the enhanced linker flexibility, provides an explanation for the mutant camptothecin resistance...
  26. pmc Topoisomerase II is a structural component of mitotic chromosome scaffolds
    W C Earnshaw
    J Cell Biol 100:1706-15. 1985
    ..Our results suggest that topoisomerase II may be an enzyme that is also a structural protein of interphase nuclei and mitotic chromosomes...
  27. pmc Topoisomerase 3alpha and RMI1 suppress somatic crossovers and are essential for resolution of meiotic recombination intermediates in Arabidopsis thaliana
    Frank Hartung
    Botany II, University of Karlsruhe, Karlsruhe, Germany
    PLoS Genet 4:e1000285. 2008
    ....
  28. ncbi Need for DNA topoisomerase activity as a swivel for DNA replication for transcription of ribosomal RNA
    S J Brill
    Nature 326:414-6. 1987
    ....
  29. pmc DNA gyrase, topoisomerase IV, and the 4-quinolones
    K Drlica
    Public Health Research Institute, New York, New York 10016, USA
    Microbiol Mol Biol Rev 61:377-92. 1997
    ..Thus, quinolone-topoisomerase biology is providing a model for understanding aspects of host-parasite interactions and providing ways to investigate manipulation of the bacterial chromosome by topoisomerases...
  30. ncbi Studies of sequence-specific DNA binding, DNA cleavage, and topoisomerase I inhibition by the dimeric chromomycin A3 complexed with Fe(II)
    Ming Hon Hou
    Biotechnology Center, National Chung Hsing University, Taichung, 402 Taiwan
    Biochemistry 47:5493-502. 2008
    ..Our results provide significant evidence that the [(Chro)2-Fe(II)] complex could be promising in terms of its biological applications in the future...
  31. pmc Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage
    John R Vance
    Plantaceutica, Incorporated, P O Box 12060, 99 Alexander Drive, Research Triangle Park, NC 27709 2060, USA
    Proc Natl Acad Sci U S A 99:13669-74. 2002
    ..Finally, we show that yeast lacking the Rad1-Rad10-related proteins Mus81-Mms4 display a unique pattern of camptothecin sensitivity and suggest a concerted model for the action of these endonucleases...
  32. ncbi Reverse gyrase and genome stability in hyperthermophilic organisms
    Giuseppe Perugino
    Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche, Via P Castellino 111, 80131 Naples, Italy
    Biochem Soc Trans 37:69-73. 2009
    ..In the present article, we review the latest progress on structure-function relationships of reverse gyrase, and discuss old and recent data linking reverse gyrase to DNA stability, protection and repair in hyperthermophilic organisms...
  33. ncbi Identification of a unique domain essential for Escherichia coli DNA topoisomerase III-catalysed decatenation of replication intermediates
    Z Li
    Department of Pharmaceutical Sciences, University of Maryland, Baltimore School of Pharmacy, 20 North Pine Street, Baltimore, MD 21201, USA
    Mol Microbiol 35:888-95. 2000
    ..The presence of this domain has been detected in multiple plasmid-encoded topoisomerases, raising the possibility that these enzymes may also be decatenases...
  34. ncbi A double Holliday junction dissolvasome comprising BLM, topoisomerase IIIalpha, and BLAP75
    Steven Raynard
    Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Biol Chem 281:13861-4. 2006
    ..This function of the BLM-Topo IIIalpha-BLAP75 dissolvasome is likely indispensable for genome maintenance and cancer avoidance...
  35. pmc Reverse gyrase has heat-protective DNA chaperone activity independent of supercoiling
    Martin Kampmann
    MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
    Nucleic Acids Res 32:3537-45. 2004
    ....
  36. ncbi Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer
    Charles S Fuchs
    Dana Farber Cancer Institute, Boston, MA 02115, USA
    J Clin Oncol 21:807-14. 2003
    ..We prospectively compared the efficacy and tolerability of two irinotecan regimens (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3 weeks) in such patients...
  37. ncbi Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell line resistant to camptothecin
    A Fujimori
    Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland 20892 4255
    Cancer Res 55:1339-46. 1995
    ..These results indicate that camptothecin resistance of CEM/C2 is due to the mutation Asn722Ser and strongly suggest that the asparagine immediately flanking the catalytic tyrosine is important for the camptothecin action...
  38. pmc Topoisomerase III is essential for accurate nuclear division in Schizosaccharomyces pombe
    A Goodwin
    Imperial Cancer Research Fund Laboratories, London, UK
    Nucleic Acids Res 27:4050-8. 1999
    ..Our data are consistent with a model in which the association of a RecQ helicase and topoisomerase III is important for facilitating decatenation of late stage replicons to permit faithful chromosome segregation during anaphase...
  39. ncbi Studies of a positive supercoiling machine. Nucleotide hydrolysis and a multifunctional "latch" in the mechanism of reverse gyrase
    A Chapin Rodriguez
    Medical Research Council Laboratory of Molecular Biology, Hills Rd, Cambridge CB2 2QH, United Kingdom
    J Biol Chem 277:29865-73. 2002
    ..This suggests that the mechanism of reverse gyrase is best described by a combination of recently proposed models...
  40. ncbi Two separate conserved domains of eukaryotic DNA topoisomerase I bind to each other and reconstitute enzymatic activity
    H Park
    Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, NY 11794 5215, USA
    Chromosoma 107:211-5. 1998
    ..The results demonstrate that the central domain of topoisomerase I interacts with the C-terminal domain of the protein and that these two domains reconstitute enzymatic activity in vivo, even when expressed as separate polypeptides...
  41. pmc Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease
    V Kaliraman
    Department of Molecular Biology and Biochemistry Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, USA
    Genes Dev 15:2730-40. 2001
    ..Repair of this double-strand break (DSB) by homologous recombination may be responsible for the elevated levels of sister chromatid exchange (SCE) found in BLM(-/-) cells...
  42. pmc Repair of topoisomerase I covalent complexes in the absence of the tyrosyl-DNA phosphodiesterase Tdp1
    Chunyan Liu
    Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD 20892 4034, USA
    Proc Natl Acad Sci U S A 99:14970-5. 2002
    ....
  43. ncbi Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells
    S D Desai
    Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA
    Cancer Res 61:5926-32. 2001
    ....
  44. ncbi Reverse gyrase functions as a DNA renaturase: annealing of complementary single-stranded circles and positive supercoiling of a bubble substrate
    Tao Shih Hsieh
    Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
    J Biol Chem 281:5640-7. 2006
    ..These biochemical activities also suggest that reverse gyrase can have an important biological function in sensing and eliminating unpaired regions in the genome of a hyperthermophilic organism...
  45. ncbi DNA topoisomerase I from parasitic protozoa: a potential target for chemotherapy
    R M Reguera
    Dpto Farmacología y Toxicología INTOXCAL, Universidad de Leon, Campus de Vegazana s n, 24071 Leon, Spain
    Biochim Biophys Acta 1759:117-31. 2006
    ..The present report is an up to date review of the new findings on type IB DNA topoisomerase in unicellular parasites and the role of these enzymes as targets for therapeutic agents...
  46. ncbi Investigating the role of the latch in the positive supercoiling mechanism of reverse gyrase
    A Chapin Rodriguez
    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom
    Biochemistry 42:5993-6004. 2003
    ..The latch therefore plays an important role in the communication between the two domains of reverse gyrase...
  47. pmc Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA
    F E Benson
    Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts, UK
    EMBO J 13:5764-71. 1994
    ..In contrast to yeast Rad51 protein, human Rad51 forms filaments with single-stranded DNA in the presence of ATP/ATP gamma S. These resemble the inactive form of the RecA filament which is observed in the absence of a nucleotide cofactor...
  48. ncbi Camptothecins: a review of their chemotherapeutic potential
    Hulya Ulukan
    Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210 1291, USA
    Drugs 62:2039-57. 2002
    ....
  49. ncbi Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme
    Y Pommier
    Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892 4255, USA
    Biochim Biophys Acta 1400:83-105. 1998
    ..Because of the importance of topoisomerase I as a chemotherapeutic target, we review the mechanisms of action of camptothecins and the other topoisomerase I inhibitors identified to date...
  50. ncbi Roles of topoisomerases in maintaining steady-state DNA supercoiling in Escherichia coli
    E L Zechiedrich
    Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 275:8103-13. 2000
    ..09), greatly stimulating transcription from the supercoiling sensitive leu-500 promoter and increasing the number of supercoils trapped by lambda integrase site-specific recombination...
  51. ncbi DNA topoisomerases: harnessing and constraining energy to govern chromosome topology
    Allyn J Schoeffler
    Department of Molecular and Cell Biology, California Institute for Quantitative Biology, University of California Berkeley, Berkeley, CA, USA
    Q Rev Biophys 41:41-101. 2008
    ....
  52. ncbi Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes
    J J Pouliot
    Laboratory of Molecular Biology, National Institute of Mental Health, Building 36, Room 1B08, Bethesda, MD 20892 4034, USA
    Science 286:552-5. 1999
    ..The presence of this gene in humans may have implications for the effectiveness of topoisomerase I poisons, such as the camptothecins, in chemotherapy...
  53. ncbi Reverse gyrase, the two domains intimately cooperate to promote positive supercoiling
    A C Déclais
    Laboratoire d Enzymologie des Acides Nucleiques, Institut de Genetique et Microbiologie, UMR 8621 CNRS, Bat 400, Universite de Paris Sud, Centre d Orsay, 91 405 Orsay Cedex, France
    J Biol Chem 275:19498-504. 2000
    ..These results suggest that the N-terminal domain does not directly unwind DNA but acts more likely by driving ATP-dependent conformational changes within the whole enzyme, reminiscent of a protein motor...
  54. ncbi Crystal structure of a complex of a type IA DNA topoisomerase with a single-stranded DNA molecule
    A Changela
    Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois 60208, USA
    Nature 411:1077-81. 2001
    ..These findings confirm various aspects of the type IA topoisomerase mechanism while suggesting functional implications for other topoisomerases and proteins that perform DNA rearrangements...
  55. pmc A new human topoisomerase III that interacts with SGS1 protein
    S W Ng
    Laboratory of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women s Hospital, 221 Longwood Avenue, Boston, MA 02115, USA
    Nucleic Acids Res 27:993-1000. 1999
    ..The presence of more than one human topoisomerase III is reminiscent of mammalian topoisomerase II, which has two genetically distinct isoforms with different expression patterns and probably different functions in mammalian cells...
  56. ncbi Adenosine 5'-O-(3-thio)triphosphate (ATPgammaS) promotes positive supercoiling of DNA by T. maritima reverse gyrase
    Stefan P Jungblut
    University of Basel, Biozentrum, Dept of Biophysical Chemistry, Klingelbergstrasse 70, CH 4056 Basel, Switzerland
    J Mol Biol 371:197-209. 2007
    ....
  57. ncbi RecQ helicase stimulates both DNA catenation and changes in DNA topology by topoisomerase III
    Frank G Harmon
    Division of Biological Sciences, Section of Microbiology, Center for Genetics and Development, University of California Davis, 1 Shields Avenue, Davis, CA 95616, USA
    J Biol Chem 278:42668-78. 2003
    ..Together our results demonstrate that RecQ helicase and Topo III function together to comprise a potent and concerted single-strand DNA passage activity that can mediate both catenation-decatenation processes and changes in DNA topology...
  58. ncbi Repair of and checkpoint response to topoisomerase I-mediated DNA damage
    Yves Pommier
    Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute NIH, Building 37, Room 5068, Bethesda, MD 20892 4255, USA
    Mutat Res 532:173-203. 2003
    ..Defects in these repair/checkpoint pathways, which promote tumor development, explain, at least in part, the selectivity of camptothecins and other Top1 inhibitors for cancer cells...
  59. ncbi BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells
    C H Yang
    Department of Oncology, National Taiwan University Hospital and the Graduate Institute of Medicine, Medical College, National Taiwan University, Taipei
    Biochem Pharmacol 60:831-7. 2000
    ..Our data suggest that enhanced topotecan efflux contributes partly to topotecan resistance in MCF7/TPT300 cells, possibly mediated by BCRP/MXR/ABCP...
  60. pmc The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase
    S Gangloff
    Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York 10032
    Mol Cell Biol 14:8391-8. 1994
    ....
  61. pmc Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors
    A C McDonald
    CRC Department of Medical Oncology, CRC Beatson Laboratories, Glasgow, UK
    Br J Cancer 78:745-51. 1998
    ..Thus, although p53-dependent apoptosis is induced by camptothecin, topotecan and SN-38 in this human ovarian carcinoma cell line, these drugs induce p53-independent death, as measured by clonogenic assay...
  62. ncbi Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA
    M R Redinbo
    Biomolecular Structure Center and Department of Biological Structure, Box 357742, School of Medicine, University of Washington, Seattle, WA 98195, USA
    Science 279:1504-13. 1998
    ..A binding mode for the anticancer drug camptothecin is proposed on the basis of chemical and biochemical information combined with these three-dimensional structures of topoisomerase I-DNA complexes...
  63. ncbi Clinical applications of the camptothecins
    C H Takimoto
    Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Building 8, Room 5101, Bethesda Naval Hospital, Bethesda, MD 20892, USA
    Biochim Biophys Acta 1400:107-19. 1998
    ..The successful development of the camptothecins as antitumor agents highlights the importance of topoisomerase I as a target for cancer chemotherapy...
  64. ncbi Reconstitution and functional characterization of the unusual bi-subunit type I DNA topoisomerase from Leishmania donovani
    Benu Brata Das
    Department of Molecular Parasitology, Indian Institute of Chemical Biology 4, Raja S C Mullick Road, Kolkata 700032, India
    FEBS Lett 565:81-8. 2004
    ..Interaction between the two subunits leading to the formation of an active complex could be explored as an insight for development of new therapeutic agents with specific selectivity...
  65. ncbi Cloning, expression, purification and characterization of DNA topoisomerase I of Mycobacterium tuberculosis
    F Yang
    Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA
    Gene 178:63-9. 1996
    ..Unlike the more well-characterized E. coli Topo I, MTb Topo I does not contain a zinc-finger DNA-binding motif in the C-terminal domain of the protein...
  66. ncbi Functional cooperation between topoisomerase I and single strand DNA-binding protein
    D Sikder
    Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560012, India
    J Mol Biol 306:669-79. 2001
    ..The stimulation is specific to topoisomerase I, as DNA gyrase activity is unaffected by SSB. We propose that such cases of functional collaboration between DNA transaction proteins play important roles in vivo...
  67. ncbi Persistence of camptothecin analog-topoisomerase I-DNA ternary complexes: a molecular dynamics study
    Fung Ming Siu
    Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China
    J Am Chem Soc 130:17928-37. 2008
    ....
  68. ncbi Evodiamine stabilizes topoisomerase I-DNA cleavable complex to inhibit topoisomerase I activity
    Agnes L F Chan
    Pharmacy Department, Chi Mei Medical Center, Tainan 710, Taiwan
    Molecules 14:1342-52. 2009
    ..2% in cells treated with 30 microM. The results suggest that EVO inhibits TopI by stabilizing the enzyme and DNA covalent complex...
  69. pmc Human TOP3: a single-copy gene encoding DNA topoisomerase III
    R Hanai
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02139, USA
    Proc Natl Acad Sci U S A 93:3653-7. 1996
    ..Screening of a panel of human-rodent somatic hybrids and fluorescence in situ hybridization of cloned TOP3 genomic DNA to metaphase chromosomes indicate that human TOP3 is a single-copy gene located at chromosome 17p11.2-12...
  70. ncbi Global transcription regulation by DNA topoisomerase I in exponentially growing Saccharomyces cerevisiae cells: activation of telomere-proximal genes by TOP1 deletion
    Luca Lotito
    Department of Biochemistry G Moruzzi, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
    J Mol Biol 377:311-22. 2008
    ..As telomere-proximal regions are known to be enriched for stress-activated genes, our findings show that Top1p can optimize transcript levels for cell growth in exponentially growing cells under a synthetic medium with glucose...
  71. ncbi Exploring DNA topoisomerases as targets of novel therapeutic agents in the treatment of infectious diseases
    Y C Tse-Dinh
    Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
    Infect Disord Drug Targets 7:3-9. 2007
    ..These new developments of DNA topoisomerases as targets of novel therapeutic agents being reviewed here represent excellent opportunities for drug discovery in the treatment of infectious diseases...
  72. pmc An RNA topoisomerase
    H Wang
    Department of Chemistry, New York University, NY 10003, USA
    Proc Natl Acad Sci U S A 93:9477-82. 1996
    ..The conversion of circles to knots is accompanied by a small amount of RNA catenane generation. These findings suggest that strand passage must be considered a potential component of the folding and modification of RNA structures...
  73. pmc The top3(+) gene is essential in Schizosaccharomyces pombe and the lethality associated with its loss is caused by Rad12 helicase activity
    M Maftahi
    Division of Environmental Sciences, Joseph Mailman School of Public Health, New York, NY 10032, USA
    Nucleic Acids Res 27:4715-24. 1999
    ..The low viability of rad12 (-) top3 (-)mutants compared with rad12 single mutants suggests that Top3 also functions independently of Rad12...
  74. ncbi Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan
    Junji Tsurutani
    Fourth Department of Internal Medicine, Kinki University School of Medicine, Ohonohigashi 377 2, Osakasayama, Osaka 589 8511, Japan
    Lung Cancer 35:299-304. 2002
    ..However, the significance of top1 mutations to CPT resistance needs to be further investigated...
  75. ncbi Cloning of the TIS gene suppressed by topoisomerase inhibitors
    Y Onishi
    Department of Biochemistry, Tokyo Dental College, Masago 1 2 2, Mihama ku, Chiba 261 8502, Japan
    Gene 215:453-9. 1998
    ..Considering that topoisomerase I is an essential enzyme in mammalian cells, the TIS protein may have an important role in camptothecin toxicity...
  76. ncbi Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts
    Annamaria Rapisarda
    Science Applications International Corporation Frederick, Inc, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA
    Cancer Res 64:6845-8. 2004
    ..These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients...
  77. ncbi Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1
    Sherif F El-Khamisy
    Genome Damage and Stability Centre, University of Sussex, Science Park Road, Falmer, Brighton BN1 9RQ, UK
    Nature 434:108-13. 2005
    ..These data identify a defect in SSBR in a neurodegenerative disease, and implicate this process in the maintenance of genetic integrity in post-mitotic neurons...
  78. ncbi Complete nucleotide sequence of the topA gene encoding Escherichia coli DNA topoisomerase I
    Y C Tse-Dinh
    J Mol Biol 191:321-31. 1986
    ..Mapping of promoters by deletion of sequences upstream from the ATG initiation codon indicates the existence of at least two promoters that direct transcription into topA...
  79. ncbi Cloning of cDNA encoding a novel mouse DNA topoisomerase III (Topo IIIbeta) possessing negatively supercoiled DNA relaxing activity, whose message is highly expressed in the testis
    T Seki
    Department of Molecular Cell Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai 980 8578, Japan
    J Biol Chem 273:28553-6. 1998
    ..The levels of TOP3beta mRNA in the testis increased slightly 14 days and considerably 17 days after birth, when the cells in the pachytene phase begin to appear and increase...
  80. pmc A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome
    Amom Ruhikanta Meetei
    Laboratory of Genetics Mass Spectrometry Unit, National Institute on Aging NIH, TRIAD Center Room 3000, 333 Cassell Drive, Baltimore, MD 21224, USA
    Mol Cell Biol 23:3417-26. 2003
    ..The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair...
  81. pmc Resolution of converging replication forks by RecQ and topoisomerase III
    Catherine Suski
    Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Mol Cell 30:779-89. 2008
    ..This resolution reaction is specific for the RecQ-topoisomerase III pair and is mediated by interaction of both of these enzymes with the single-stranded DNA-binding protein SSB...
  82. pmc Topoisomerase II, not topoisomerase I, is the proficient relaxase of nucleosomal DNA
    Javier Salceda
    Institut de Biologia Molecular de Barcelona, CSIC, Barcelona, Spain
    EMBO J 25:2575-83. 2006
    ..We conclude that topoisomerase II is the main modulator of DNA topology in chromatin fibers. The nonessential topoisomerase I then assists DNA relaxation where chromatin structure impairs DNA juxtaposition but allows twist diffusion...
  83. pmc Topoisomerase IIIalpha is required for normal proliferation and telomere stability in alternative lengthening of telomeres
    Nassima Temime-Smaali
    Laboratoire d Onco Pharmacologie, JE 2428, UFR de Pharmacie, Universite de Reims Champagne Ardenne, Reims, France
    EMBO J 27:1513-24. 2008
    ..We conclude that Topo IIIalpha is an important telomere-associated factor, essential for telomere maintenance and chromosome stability in ALT cells, and speculate on its potential mechanistic function...
  84. ncbi Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes
    Ze Hong Miao
    Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
    DNA Repair (Amst) 5:1489-94. 2006
    ....
  85. ncbi A TOPRIM domain in the crystal structure of the catalytic core of Escherichia coli primase confirms a structural link to DNA topoisomerases
    M Podobnik
    Laboratories of Molecular Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA
    J Mol Biol 300:353-62. 2000
    ..The catalytic domain of primase is crescent-shaped, and the concave face of the crescent is predicted to accommodate about 10 base-pairs of RNA-DNA duplex in a loose interaction, thereby limiting processivity...
  86. ncbi Friction and torque govern the relaxation of DNA supercoils by eukaryotic topoisomerase IB
    Daniel A Koster
    Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
    Nature 434:671-4. 2005
    ..We propose a model for topoisomerization in which the torque drives the DNA rotation over a rugged periodic energy landscape in which the topoisomerase has a small but quantifiable probability to religate the DNA once per turn...
  87. pmc Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes
    R G Shao
    Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 4255, USA
    EMBO J 18:1397-406. 1999
    ....
  88. pmc BLAP75/RMI1 promotes the BLM-dependent dissolution of homologous recombination intermediates
    Leonard Wu
    Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom
    Proc Natl Acad Sci U S A 103:4068-73. 2006
    ..Implications of the conserved ability of type IA topoisomerases to catalyze dissolution and how the evolution of factors such as BLAP75/RMI1 might confer specificity on the execution of this process are discussed...
  89. ncbi Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex
    Bart L Staker
    deCODE BioStructures, 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA
    J Med Chem 48:2336-45. 2005
    ..These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs...
  90. ncbi Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin
    Jonathan P Carson
    Department of Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts, USA
    Cancer Res 64:2096-104. 2004
    ....
  91. pmc Binding and activation of DNA topoisomerase III by the Rmi1 subunit
    Chi Fu Chen
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854, USA
    J Biol Chem 282:28971-9. 2007
    ..These results demonstrate that Top3-Rmi1 functions as a complex and suggest that Rmi1 stimulates Top3 by promoting its interaction with ssDNA...
  92. pmc Bipartite structure of the SGS1 DNA helicase in Saccharomyces cerevisiae
    J R Mullen
    Department of Molecular Biology and Biochemistry, Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08855, USA
    Genetics 154:1101-14. 2000
    ..We conclude that the amino terminus of Sgs1 has an essential role in SGS1 function, distinct from that of the DNA helicase, with which it genetically interacts...
  93. ncbi Phase I and pharmacologic study of infusional topotecan and Carboplatin in relapsed and refractory acute leukemia
    Scott H Kaufmann
    Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55901, USA
    Clin Cancer Res 11:6641-9. 2005
    ..To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias...
  94. ncbi Caspase-mediated cleavage of DNA topoisomerase I at unconventional sites during apoptosis
    K Samejima
    Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh EH9 3JR, Scotland, United Kingdom
    J Biol Chem 274:4335-40. 1999
    ....
  95. ncbi Synergistic interactions of combinations of topotecan with standard drugs in primary cultures of human tumor cells from patients
    E Jonsson
    Division of Clinical Pharmacology, Uppsala University Hospital, Sweden
    Eur J Clin Pharmacol 54:509-14. 1998
    ..Combination therapies are important in the treatment of many tumor types. This study was undertaken to find candidates for combination therapy with the novel topoisomerase I inhibitor topotecan...
  96. ncbi Antitopoisomerase 1 antibodies in systemic sclerosis: how to improve the detection?
    Mathieu C Tamby
    Paris Descartes University, Faculty of Medicine, UPRES EA 4058 Site Cochin, Paris, France
    Ann N Y Acad Sci 1109:221-8. 2007
    ..Thus, we may propose that a combination of the immunoblot using HEp-2 cells antigens and ELISA could be used for the detection of ATA...
  97. pmc Mutations in homologous recombination genes rescue top3 slow growth in Saccharomyces cerevisiae
    Erika Shor
    Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York 10032 2704, USA
    Genetics 162:647-62. 2002
    ..We present a model wherein Rad51 helps recruit Sgs1-Top3 to sites of replicative damage...
  98. pmc Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts
    G Vassal
    Department of Pediatric Oncology, Institut Gustave Roussy, Villejuif, France
    Br J Cancer 74:537-45. 1996
    ..In conclusion, CPT-11 demonstrated significant activity against pPNET and neuroblastoma xenografts. Further clinical development of CPT-11 in paediatric oncology is warranted...
  99. ncbi The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells
    S Jacob
    , Institut Gustave Roussy, 94 800 Villejuif, France
    Cancer Res 61:6555-62. 2001
    ..Interestingly, our observations provide the rationale for the better responsiveness of MSI+ tumors to CPT-11, a camptothecin derivative, which we have observed in patients with metastatic colorectal cancers...
  100. ncbi Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity
    Y Xu
    Department of Medicine and the Experimental Therapeutics Program, Comprehensive Cancer Center, Arthur G James Cancer Hospital, Columbus, OH, USA
    Ann Oncol 13:1841-51. 2002
    ....
  101. ncbi A model for the mechanism of human topoisomerase I
    L Stewart
    Biomolecular Structure Center and Department of Biological Structure, School of Medicine, University of Washington, Seattle, WA 98195 7742, USA
    Science 279:1534-41. 1998
    ..The structures also lead to the proposal that the topoisomerization step occurs by a mechanism termed "controlled rotation."..

Research Grants64

  1. HTS assay development targeting Yersinia pestis topoisomerase I
    Yuk Ching Tse-Dinh; Fiscal Year: 2011
    ....
  2. Role of c-Met in SCLC and Potential for Novel Therapy
    Ravi Salgia; Fiscal Year: 2012
    ..In the nucleus, it binds to different proteins such as Pax5 and topoisomerase-I, and the studies proposed will dissect out mechanisms for this. Ultimately, we propose to bring to fruition combination therapies using these molecules. ..
  3. Novel Topoisomerase I Inhibitors
    MARK S CUSHMAN; Fiscal Year: 2013
    ....
  4. Ras18-mediated Fanconi Anemia pathway activation in response to camptothecin
    Komaraiah Palle; Fiscal Year: 2013
    ....
  5. Analysis of replication fork-collapse in yeast by site-specific DNA nicking
    RANJITH PRASAD ANAND; Fiscal Year: 2013
    ..This project will, for the first time, enable a detailed real-time study of the molecular events when a DNA replication fork encounters different types of template strand interruptions. ..
  6. MECHANISM OF ACTION OF ANTITUMOR DRUGS
    Leroy F Liu; Fiscal Year: 2013
    ..Successful completion of the proposed studies will not only advance our understanding of the mechanism of action of Top1-targeting drugs but also may lead to development of better treatment strategies for Top1 drug-based cancer therapy. ..
  7. Novel Mechanisms by which RAD18 and POLZ affect Response to Anticancer Agents
    CHRISTINE ELIZABETH CANMAN; Fiscal Year: 2012
    ....
  8. 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. ..
  9. In situ assay for DNA cleavage by topoisomerase II
    BENXIAO ZHANG; Fiscal Year: 2011
    ..The technology will allow precise evaluation of the effects of therapy in diseases where cell death and DNA damage have prognostic value, such as various cancers, including glioblastoma, as well as stroke and Alzheimer's disease. ..
  10. Mayo Clinic SPORE in Ovarian Cancer
    Scott H Kaufmann; Fiscal Year: 2013
    ..The Mayo Clinic SPORE in Ovarian Cancer has the full support of the Mayo Clinic Cancer Center and Mayo Foundation. ..
  11. 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. ..
  12. Regulation and Function of the p14ARF/topoisomerase I Complex in Cancer
    Ruth A Gjerset; Fiscal Year: 2012
    ....
  13. Tumorigenic Role of the CUL4A Ubiquitin Ligase
    Pengbo Zhou; Fiscal Year: 2013
    ..abstract_text> ..
  14. Selective Inhibitors to Improve CPT-11 Therapy
    Philip M Potter; Fiscal Year: 2013
    ..This would likely result in improved antitumor efficacy and furthermore, may also allow use of this CPT-11 against more resistant malignancies that demonstrate marginal response to this agent. ..
  15. Pathways fo Lambda Site-Specific Recombination
    ANCA MARA SEGALL; Fiscal Year: 2010
    ..The new characterization will include structural studies of the inhibitors. ..
  16. Evaluation and development of E1-TopoI as a target for anti-HPV therapeutics
    Thomas Melendy; Fiscal Year: 2013
    ..Results will provide chemical and structural information that will be used in developing second-generation inhibitors that will be investigated as potential antiviral therapeutics against papillomaviruses. ..
  17. Bacterial cell killing by topoisomerase I mediated DNA lesion
    Yuk Ching Tse-Dinh; Fiscal Year: 2013
    ..Success in these proposed experiments would provide tools and leads for development of novel antibacterial drugs for the urgent public health problem of bacterial pathogens resistant to all current antibiotics. ..
  18. Humanized Anti-Trop2-SN-38 Conjugate For Advanced Pancreatic Cancer
    William A Wegener; Fiscal Year: 2012
    ....
  19. Modulation of drug metabolism by Danshen
    Philip M Potter; Fiscal Year: 2013
    ..We envisage that the studies proposed here will validate this hypothesis and provide information concerning the use of such extracts in defined patient populations. ..
  20. HTLV-I Tax induces DNA breaks and inhibits HR repair through activation of NF-kB
    CHRISTOPHE P NICOT; Fiscal Year: 2013
    ..This project will elucidate the mechanisms employed by Tax to increase genetic instability in pre-tumoral cells and the cellular genes involved in the adaptation/tolerance of DNA damage and transformation. ..
  21. Novel Direct Approaches Toward Bioactive Heterocycles
    Vladimir Gevorgyan; Fiscal Year: 2013
    ....
  22. Optimization of dipeptide-linked benzimidazole topoisomerase 1 poisons
    Craig Beeson; Fiscal Year: 2009
    ..Because these agents are also structurally distinct, it is expected that they will be clinically efficacious against cancers that have developed resistance to the camptothecins. ..
  23. DRUG SEQUENCING RESISTANCE IN MULTIPLE MYELOMA
    Daniel Sullivan; Fiscal Year: 1999
    ....
  24. Targeting Cell Cycle Checkpoints in Cancer Therapeutics
    Archie Tse; Fiscal Year: 2009
    ..The proposed studies are expected to provide insights of how checkpoint defects in tumors can be exploited to render them more susceptible to combined treatment with chemotherapy and checkpoint inhibitors such as 17AAG. ..
  25. SAR OF NOVEL TOPO I INHIBITOR AGAINST PROSTATE CANCER
    YUE WEI LEE; Fiscal Year: 2001
    ..abstract_text> ..
  26. Anti-Cancer Drug Design Targeting Human Topoisomerase I
    Lance Stewart; Fiscal Year: 2002
    ..The most promising compounds will be examined for their efficacy in stopping human tumor growth in the mouse xenotransplant model. PROPOSED COMMERCIAL APPLICATION: Not available ..
  27. Chinese Herbal Medicine as a Novel Paradigm for Cancer Chemotherapy
    Yung Chi Cheng; Fiscal Year: 2013
    ..abstract_text> ..
  28. MOLECULAR MECHANISMS IN SCLERODERMA--SCL-70/TOPO I
    Angeline Douvas; Fiscal Year: 1990
    ..Based on the outcome of these studies it may be possible to design more specific and effective therapies for this disorder...
  29. The meiotic role of dtopors in male Drosophila
    JOHN TOMKIEL; Fiscal Year: 2007
    ..unreadable] [unreadable] [unreadable]..
  30. Human RecQ helicases in biology and oncology
    Raymond J Monnat; Fiscal Year: 2013
    ..Thus the proposed research will have substantial basic science, clinical and translational potential. We plan to fully develop these opportunities in the proposed research. ..
  31. MOLECULAR PROGNOSTIC INDICATORS IN COLORECTAL CANCER
    Leonard Saltz; Fiscal Year: 2000
    ....
  32. STRUCTURE/FUNCTION OF TWO DNA BINDING PROTEINS
    WILHELMUS HOL; Fiscal Year: 2004
    ..tuberculosis), and (iii) the most devastating eukaryotic parasite (P. falciparum) known. The latter two account for roughly five million deaths per year worldwide. ..
  33. Benzo[i]phenanthridines: TOP1-Targeting Antitumor Agents
    EDMOND LAVOIE; Fiscal Year: 2006
    ..unreadable] [unreadable]..
  34. MECHANISM BASED PHASE I TRIAL OF TOPOTECAN IN LEUKEMIA
    Brenda Cooper; Fiscal Year: 2000
    ..These studies will provide a model for designing strategies to optimize safety and efficacy of treatment regimens for patients with acute leukemia. ..
  35. GENOME ORGANIZATION--COORDINATED GENE EXPRESSION
    Hai Young Wu; Fiscal Year: 2000
    ..This research is likely to impact on various aspects of medical genetic research as the proposed studies will reveal a novel gene expression regulatory mechanism involving transcription- mediated DNA supercoiling. ..
  36. Radioisotope Therapy Targeting the Somatostatin Receptor
    Gina Chung; Fiscal Year: 2003
    ..These translational studies will serve as the basis for expanding a novel therapeutic modality for neuroendocrine cancers. ..
  37. METHODS TO IMPROVE CAMPTOTHECAN BASED CHEMOTHERAPY
    OLIVER COLVIN; Fiscal Year: 2000
    ..Since this strategy is clinically feasible, there is significant potential for rapid translation of this work to clinical oncology. ..
  38. TOPOISOMERASE DRUG ACTIONS AT NUCLEAR MATRIX DNA DOMAIN
    Daniel Fernandes; Fiscal Year: 2003
    ....
  39. TOPOISOMERASE I STRUCTURE AND REGULATION
    Eric Rubin; Fiscal Year: 1999
    ..Additional studies will attempt to identify other binding proteins and to investigate the effects of these proteins on topoisomerase I function and on the interaction between topoisomerase I and inhibitors such as camptothecin. ..
  40. GYNECOLOGIC MALIGNANCIES--NOVEL PHASE II AGENTS
    Scott Wadler; Fiscal Year: 2000
    ....
  41. PHASE II TRIALS OF TOPO I INHIBITORS
    Nathan Berger; Fiscal Year: 2000
    ....
  42. Topoisomerase Targeting and Resistance in Leukemia
    Eric Rubin; Fiscal Year: 2003
    ..The results of these studies should provide insight into clinical mechanisms of resistance to topotecan, and allow rational development of a topoisomerase-targeting strategy in the treatment of leukemia. ..
  43. ANTICANCER COMPOUNDS DESIGNED TO POISON TOPOISOMERASE I
    Lance Stewart; Fiscal Year: 2000
    ..In addition, the information gained from the X-ray structure determinations of the human topo I- poison complexes would form the basis for several patient applications on totally new classes of topo I poisons. ..
  44. REGULATION OF DNA IN CAMPTOTHECIN TREATED CELLS
    Ya Wang; Fiscal Year: 2002
    ..The proposed research is based on information from preliminary results and combines current knowledge on the DNA replication and CPT cytotoxicity to characterize the modulation of DNA replication in CPT-treated cells. ..
  45. FUNCTIONAL STUDIES OF TOPOISOMERASE I
    Eric Rubin; Fiscal Year: 2002
    ..Collectively, these studies should provide information valuable not only for understanding the cellular role of topoisomerase I but also for elucidating the cytotoxic mechanisms of camptothecin. ..
  46. DNA TOPOISOMERASE I TARGET INTERACTIONS OF CAMPTOTHECINS
    Danzhou Yang; Fiscal Year: 2004
    ..This research project is intended to define the academic research program of Dr. Yang who is intent on achieving a faculty position in a first- rate research-oriented College of Pharmacy or Medicine in the United States. ..
  47. MECHANISMS OF SUPPRESSING CAMPTOTHECIN TOXICITY
    Mary Ann Bjornsti; Fiscal Year: 2003
    ..These studies will provide insight into the ability of Top1-targeted drugs to induce tumors in pediatric and adult populations. ..
  48. NOVEL A RING AND E RING MODIFIED CAMPTOTHECIN ANALOGS
    Daniel Von Hoff; Fiscal Year: 2001
    ..abstract_text> ..
  49. TOPOTECAN BY INTRACEREBRAL CLYSIS FOR BRAIN TUMORS
    Jeffrey Bruce; Fiscal Year: 2006
    ..abstract_text> ..
  50. SUMOylation and Cell Sensitivity to Top1 Poisons
    Mary Ann Bjornsti; Fiscal Year: 2009
    ..Human/yeast Ubc9p chimeras will further define residues that dictate substrate specificity. Additional studies will determine if similar mechanisms regulate ulp2Adelta cell sensitivity to Top1p levels and genomic stability. ..
  51. Potent Topoisomerase I Inhibition For Glioma Therapy
    Thomas Burke; Fiscal Year: 2001
    ....
  52. SYNTHESIS OF INDOLOCARBAZOLES AS TOPOISOMERASE I POISONS
    David Zembower; Fiscal Year: 2000
    ..Such as agent could be used alone or in combination with existing antitumor agents, especially in patients who develop resistance to existing medications. ..
  53. A Two Hybrid System Based Yeasy Screen for Agents that Affect DNA Damage Checkpoi
    Nalin Kumar; Fiscal Year: 2007
    ..unreadable] [unreadable] [unreadable]..
  54. MUTATIONAL ANALYSIS OF E COLI DNA TOPOISOMERASE III
    Russell DiGate; Fiscal Year: 2005
    ..Elucidate the role of E. coli Topo III in recombination 3. Identify and examine the role of topoisomerase III interactions with other cellular proteins, in particular, DNA helicases. ..
  55. ROLE OF TOPOISOMERASE I IN DNA REPAIR AND CHEMOTHERAPY
    ARTHUR PARDEE; Fiscal Year: 1993
    ....
  56. TOPOISOMERASE I AS AN ANTITUMOR DRUG TARGET
    PETER D ARPA; Fiscal Year: 1999
    ....
  57. TOPOISOMERASE TARGETED AGENTS--CHEMISTRY TO CHEMOTHERAPY
    David Graves; Fiscal Year: 2000
    ..This symposium will bring together a diverse group of scientists and clinicians and will focus on the design, development, and mechanism of action of topoisomerase-targeted chemotherapeutic agents. ..
  58. CLINICAL TRIAL OF IRINOTECAN IN COLON CANCER
    James Willson; Fiscal Year: 1999
    ....
  59. Functional studies of the top 1-binding protein topors
    Eric Rubin; Fiscal Year: 2006
    ..The proposed experiments should significantly increase current knowledge regarding the function of topors and may lead to new strategies in the prevention and treatment of cancer [unreadable] [unreadable]..
  60. HUMAN TOPO I--AN EXPLOITABLE ANTICANCER DRUG TARGET
    James Abbruzzese; Fiscal Year: 1992
    ....
  61. REGULATION OF DNA SUPERCOILING IN BACTERIA
    Gail Pruss; Fiscal Year: 1990
    ..This work should help to understand the interactions involved in regulating DNA supercoiling and lead to an increased understanding of the in vivo role(s) of topoisomerase I...
  62. Potentiation of Topoisomerase I Inhibitors
    Jing Zhen Deng; Fiscal Year: 2002
    ..The annual market for an agents. The annual market for an agent of this type should be well in excess of $100 million. ..
  63. Novel Camptothecins with DNA Binding Activity
    Li ming Zhou; Fiscal Year: 2001
    ..With acceptable pharmacokinetic and toxicological profiles, new anticancer agents could find enormous commercial applications, and provide alternative therapeutical management for patients resistant to existing anticancer drugs. ..
  64. Development of a HTS system:topoisomerase targets (RMI)
    Yuk Ching Tse Dinh; Fiscal Year: 2004
    ..The screening system should also be applicable for targeting topoisomerases in pathogenic bacteria relevant for biodefense. ..