type ii dna topoisomerases

Summary

Summary: DNA TOPOISOMERASES that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex.

Top Publications

  1. Bates A, Maxwell A. The role of ATP in the reactions of type II DNA topoisomerases. Biochem Soc Trans. 2010;38:438-42 pubmed publisher
    b>Type II DNA topoisomerases catalyse changes in DNA topology in reactions coupled to the hydrolysis of ATP. In the case of DNA gyrase, which can introduce supercoils into DNA, the requirement for free energy is clear...
  2. Baldwin E, Osheroff N. Etoposide, topoisomerase II and cancer. Curr Med Chem Anticancer Agents. 2005;5:363-72 pubmed
  3. Bender R, 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. 2007;20:975-81 pubmed
    ..These findings strongly support the hypothesis that the ability of quinones to block the N-terminal gate of the type II enzyme contributes to their actions as topoisomerase II poisons. ..
  4. Cuvier O, Stanojcic S, Lemaitre J, Mechali M. A topoisomerase II-dependent mechanism for resetting replicons at the S-M-phase transition. Genes Dev. 2008;22:860-5 pubmed publisher
    ..Our results show that ORC1 degradation is rescued by Pin1 depletion and that this topo II-dependent clearing of ORC1/2 from chromatin involves the APC. ..
  5. Marko J. Micromechanical studies of mitotic chromosomes. Chromosome Res. 2008;16:469-97 pubmed publisher
    ..The as-yet unresolved questions of the identities of the putative chromatin crosslinkers and their organization inside mitotic chromosomes are discussed. ..
  6. Azarova A, Lyu Y, Lin C, Tsai Y, Lau J, Wang J, et al. Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A. 2007;104:11014-9 pubmed
    ..These results point to the importance of developing Top2alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies. ..
  7. Wilstermann A, Bender R, Godfrey M, Choi S, Anklin C, Berkowitz D, et al. Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Biochemistry. 2007;46:8217-25 pubmed
    ..The functional importance of E-ring substituents was confirmed by topoisomerase II-mediated DNA cleavage assays. ..
  8. Bates A, Maxwell A. Energy coupling in type II topoisomerases: why do they hydrolyze ATP?. Biochemistry. 2007;46:7929-41 pubmed
    ..This review discusses our current understanding of the mechanisms behind the coupling of the energy of ATP hydrolysis to topological changes catalyzed by both of these classes of enzyme. ..
  9. Nayak M, Yang J, Hait W. Effect of a single nucleotide polymorphism in the murine double minute 2 promoter (SNP309) on the sensitivity to topoisomerase II-targeting drugs. Cancer Res. 2007;67:5831-9 pubmed
    ..Given the frequency of SNP309 in the general population (40% in heterozygous T/G and 12% in homozygous G/G condition), our observation may have important implications for the individualization of cancer chemotherapy. ..

More Information

Publications73

  1. Wang L, Schwarzbraun T, Speicher M, Nigg E. Persistence of DNA threads in human anaphase cells suggests late completion of sister chromatid decatenation. Chromosoma. 2008;117:123-35 pubmed
    ..Moreover, they show that topoisomerase activity is required during anaphase for the resolution of PICH-positive threads, implying that the complete separation of sister chromatids occurs later than previously assumed. ..
  2. Martins R, Krawetz S. Decondensing the protamine domain for transcription. Proc Natl Acad Sci U S A. 2007;104:8340-5 pubmed
    ..This has provided a likely model of the events initiating potentiation, i.e., the opening of a chromatin domain. ..
  3. Toyoda E, Kagaya S, Cowell I, Kurosawa A, Kamoshita K, Nishikawa K, et al. NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform. J Biol Chem. 2008;283:23711-20 pubmed publisher
    ..We also suggest that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents. ..
  4. Tse Dinh Y. Exploring DNA topoisomerases as targets of novel therapeutic agents in the treatment of infectious diseases. Infect Disord Drug Targets. 2007;7:3-9 pubmed
    ..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. ..
  5. Deweese J, Osheroff N. The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing. Nucleic Acids Res. 2009;37:738-48 pubmed publisher
    ..Finally, it will describe dietary and environmental agents that enhance DNA cleavage mediated by the enzyme. ..
  6. Bandele O, Osheroff N. The efficacy of topoisomerase II-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells. Biochemistry. 2008;47:11900-8 pubmed publisher
    ..Taken together, these findings suggest that it may be possible to preferentially target topoisomerase IIalpha with etoposide by employing a schedule that utilizes pulsed drug treatment-recovery cycles. ..
  7. Wray J, Williamson E, Royce M, Shaheen M, Beck B, Lee S, et al. Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells. PLoS ONE. 2009;4:e5323 pubmed publisher
    ..Metnase could also become an important target for combination chemotherapy with current Topo IIalpha inhibitors, specifically in anthracycline-resistant breast cancer. ..
  8. McClendon A, Osheroff N. DNA topoisomerase II, genotoxicity, and cancer. Mutat Res. 2007;623:83-97 pubmed
    ..This article discusses both aspects of human type II topoisomerases. ..
  9. Robinson H, Bratlie Thoresen S, Brown R, Gillespie D. Chk1 is required for G2/M checkpoint response induced by the catalytic topoisomerase II inhibitor ICRF-193. Cell Cycle. 2007;6:1265-7 pubmed
  10. Bandele O, Osheroff N. Bioflavonoids as poisons of human topoisomerase II alpha and II beta. Biochemistry. 2007;46:6097-108 pubmed
    ..These data support the hypothesis that bioflavonoids function as topoisomerase II poisons in humans and provide a framework for further analysis of these important dietary components. ..
  11. Perillo B, Ombra M, Bertoni A, Cuozzo C, Sacchetti S, Sasso A, et al. DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science. 2008;319:202-6 pubmed publisher
    ..Our data show a strategy that uses controlled DNA damage and repair to guide productive transcription. ..
  12. Linka R, Porter A, Volkov A, Mielke C, Boege F, Christensen M. C-terminal regions of topoisomerase IIalpha and IIbeta determine isoform-specific functioning of the enzymes in vivo. Nucleic Acids Res. 2007;35:3810-22 pubmed
    ..Our results show that it is the CTRs of human topoisomerase II that determine their isoform-specific functions in proliferating cells. They also indicate persistence of some functional redundancy between the two isoforms. ..
  13. Bender R, Ham A, Osheroff N. Quinone-induced enhancement of DNA cleavage by human topoisomerase IIalpha: adduction of cysteine residues 392 and 405. Biochemistry. 2007;46:2856-64 pubmed
    ..These findings indicate that adduction of Cys392 and Cys405 is important for the actions of quinones against the enzyme and increases levels of cleavage complexes primarily by inhibiting DNA religation. ..
  14. Deweese J, Guengerich F, Burgin A, Osheroff N. Metal ion interactions in the DNA cleavage/ligation active site of human topoisomerase IIalpha. Biochemistry. 2009;48:8940-7 pubmed publisher
    ..Furthermore, we propose that M(1)(2+) interacts with E461, D543, and D545 and M(2)(2+) interacts with E461 and D541. ..
  15. Lyu Y, Kerrigan J, Lin C, Azarova A, Tsai Y, Ban Y, et al. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007;67:8839-46 pubmed
  16. Vologodskii A. Theoretical models of DNA topology simplification by type IIA DNA topoisomerases. Nucleic Acids Res. 2009;37:3125-33 pubmed publisher
    ..A few models, suggested to explain the phenomenon, are analyzed in this review. We also consider experimental data that both support and contravene these models. ..
  17. Stuchinskaya T, Mitchenall L, Schoeffler A, Corbett K, Berger J, Bates A, et al. How do type II topoisomerases use ATP hydrolysis to simplify DNA topology beyond equilibrium? Investigating the relaxation reaction of nonsupercoiling type II topoisomerases. J Mol Biol. 2009;385:1397-408 pubmed publisher
    ..We also speculate whether topology simplification might simply be an evolutionary relic, with no adaptive significance. ..
  18. Mueller Planitz F, Herschlag D. Coupling between ATP binding and DNA cleavage by DNA topoisomerase II: A unifying kinetic and structural mechanism. J Biol Chem. 2008;283:17463-76 pubmed publisher
  19. Bandele O, Clawson S, Osheroff N. Dietary polyphenols as topoisomerase II poisons: B ring and C ring substituents determine the mechanism of enzyme-mediated DNA cleavage enhancement. Chem Res Toxicol. 2008;21:1253-60 pubmed publisher
    ..Disruption of these elements abrogates enzyme binding and precludes the ability to function as a traditional topoisomerase II poison. ..
  20. Baxter J, Diffley J. Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast. Mol Cell. 2008;30:790-802 pubmed publisher
  21. Masliah G, René B, Zargarian L, Fermandjian S, Mauffret O. Identification of intrinsic dynamics in a DNA sequence preferentially cleaved by topoisomerase II enzyme. J Mol Biol. 2008;381:692-706 pubmed publisher
    ..The sequences could then be selected based on their facility to undertake conformational change during the complex formation, rather than purely based on binding affinity. ..
  22. Deweese J, Burgin A, Osheroff N. Using 3'-bridging phosphorothiolates to isolate the forward DNA cleavage reaction of human topoisomerase IIalpha. Biochemistry. 2008;47:4129-40 pubmed publisher
    ..Phosphorothiolate substrates provide significant advantages over traditional "suicide substrates" and should be valuable for future studies on DNA scission and the topoisomerase II-DNA cleavage complex. ..
  23. Burnier Y, Weber C, Flammini A, Stasiak A. Local selection rules that can determine specific pathways of DNA unknotting by type II DNA topoisomerases. Nucleic Acids Res. 2007;35:5223-31 pubmed
    ..of DNA chains to understand how local geometry of juxtaposed segments in knotted DNA molecules can guide type II DNA topoisomerases to perform very efficient relaxation of DNA knots...
  24. Dong K, Berger J. Structural basis for gate-DNA recognition and bending by type IIA topoisomerases. Nature. 2007;450:1201-5 pubmed
    ..Binding of DNA facilitates opening of an enzyme dimerization interface, providing visual evidence for a key step in DNA transport. ..
  25. Bandele O, Osheroff N. (-)-Epigallocatechin gallate, a major constituent of green tea, poisons human type II topoisomerases. Chem Res Toxicol. 2008;21:936-43 pubmed publisher
    ..Taken together, these results provide strong evidence that EGCG is a redox-dependent topoisomerase II poison and utilizes a mechanism similar to that of 1,4-benzoquinone. ..
  26. Abdurashidova G, Radulescu S, Sandoval O, Zahariev S, Danailov M, Demidovich A, et al. Functional interactions of DNA topoisomerases with a human replication origin. EMBO J. 2007;26:998-1009 pubmed
    ..Inhibition of topoisomerase I activity abolishes origin firing. Thus, the two topoisomerases are closely associated with the replicative complexes, and DNA topology plays an essential functional role in origin activation. ..
  27. Dawlaty M, Malureanu L, Jeganathan K, Kao E, Sustmann C, Tahk S, et al. Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIalpha. Cell. 2008;133:103-15 pubmed publisher
    ..Furthermore, mice with low amounts of RanBP2 are highly sensitive to tumor formation. Together, these data identify RanBP2 as a chromosomal instability gene that regulates Topo IIalpha by sumoylation and suppresses tumorigenesis. ..
  28. Liu Z, Deibler R, Chan H, Zechiedrich L. The why and how of DNA unlinking. Nucleic Acids Res. 2009;37:661-71 pubmed publisher
    ..We close with a discussion on recent theoretical advances indicating that the topological problems, themselves, can provide the cues necessary for their resolution by type-2 topoisomerases. ..
  29. Wray J, Williamson E, Sheema S, Lee S, Libby E, Willman C, et al. Metnase mediates chromosome decatenation in acute leukemia cells. Blood. 2009;114:1852-8 pubmed publisher
    ..Thus, Metnase expression levels may predict AML resistance to Topo IIalpha inhibitors, and Metnase is a potential therapeutic target for small molecule interference. ..
  30. Baumann C, Körner R, Hofmann K, Nigg E. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell. 2007;128:101-14 pubmed
    ..These data identify PICH as a novel essential component of checkpoint signaling. We propose that PICH binds to catenated centromere-related DNA to monitor tension developing between sister kinetochores. ..
  31. Montecucco A, Biamonti G. Cellular response to etoposide treatment. Cancer Lett. 2007;252:9-18 pubmed
    ..The elucidation of the effects of etoposide on cell metabolism will increase our ability to exploit this drug in cancer therapy and will expand our comprehension of the cancerous cell. ..
  32. McClendon A, Dickey J, 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;45:11674-80 pubmed
  33. Yanagida M. Basic mechanism of eukaryotic chromosome segregation. Philos Trans R Soc Lond B Biol Sci. 2005;360:609-21 pubmed
    ..The roles of principal players in basic chromosome segregation are discussed: most players have interphase as well as mitotic functions. A view on how the centromere/kinetochore is formed is described. ..
  34. Blattes R, Monod C, Susbielle G, Cuvier O, Wu J, Hsieh T, et al. Displacement of D1, HP1 and topoisomerase II from satellite heterochromatin by a specific polyamide. EMBO J. 2006;25:2397-408 pubmed
    ..We propose that this effect is due to displacement of the heterochromatin proteins D1, HP1 and topoisomerase II from SAT III, hence resulting in stochastic chromatin opening and desilencing of the nearby white gene. ..
  35. Toyoda Y, Yanagida M. Coordinated requirements of human topo II and cohesin for metaphase centromere alignment under Mad2-dependent spindle checkpoint surveillance. Mol Biol Cell. 2006;17:2287-302 pubmed
    ..Cohesin and topo II have distinct, yet coordinated functions in metaphase alignment. ..
  36. Liu Z, Mann J, Zechiedrich E, Chan H. Topological information embodied in local juxtaposition geometry provides a statistical mechanical basis for unknotting by type-2 DNA topoisomerases. J Mol Biol. 2006;361:268-85 pubmed
    ..These quantitative findings suggest that it is possible for topoisomerases to disentangle by acting selectively on juxtapositions with "hooked" geometries. ..
  37. Schoeffler A, Berger J. Recent advances in understanding structure-function relationships in the type II topoisomerase mechanism. Biochem Soc Trans. 2005;33:1465-70 pubmed
    ..Taken together, these findings expand our understanding of how disparate functional elements work together to co-ordinate the type II topo mechanism. ..
  38. Lyu Y, Lin C, Azarova A, Cai L, Wang J, Liu L. Role of topoisomerase IIbeta in the expression of developmentally regulated genes. Mol Cell Biol. 2006;26:7929-41 pubmed
    ..Together, these results support a role of TopIIbeta in activation/repression of developmentally regulated genes at late stages of neuronal differentiation. ..
  39. Dickey J, Osheroff N. Impact of the C-terminal domain of topoisomerase IIalpha on the DNA cleavage activity of the human enzyme. Biochemistry. 2005;44:11546-54 pubmed
    ..Therefore, the C-terminal domain of human topoisomerase IIalpha appears to play significant roles in modulating the DNA cleavage/ligation reaction of the enzyme and its response to anticancer agents. ..
  40. Stray J, Crisona N, Belotserkovskii B, Lindsley J, Cozzarelli N. The Saccharomyces cerevisiae Smc2/4 condensin compacts DNA into (+) chiral structures without net supercoiling. J Biol Chem. 2005;280:34723-34 pubmed
    ..quot; Close packing of Smc2/4 on DNA explains the substrate protection we observed. Our results support the hypothesis that SMC proteins bind multiple DNA duplexes. ..
  41. Spence J, Fournier R, Oshimura M, Regnier V, Farr C. Topoisomerase II cleavage activity within the human D11Z1 and DXZ1 alpha-satellite arrays. Chromosome Res. 2005;13:637-48 pubmed
    ..We also demonstrate that catalytically active Topo II is concentrated within the centromere domain through an extended period of G2 and M, with levels declining in G1 and S. ..
  42. Mistry A, Felix C, Whitmarsh R, Mason A, Reiter A, Cassinat B, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med. 2005;352:1529-38 pubmed
    ..Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with other topoisomerase II poisons. ..
  43. Gruber B, Anuszewska E, Bubko I, Gozdzik A, Priebe W, Fokt I. Relationship between topoisomerase II-DNA cleavable complexes, apoptosis and cytotoxic activity of anthracyclines in human cervix carcinoma cells. Anticancer Res. 2005;25:2193-8 pubmed
    ..The efficiency of anthracycline antibiotics, interpreted as cytotoxic action, was dependent on cell type. ..
  44. Takahashi Y, Yong Gonzalez V, Kikuchi Y, Strunnikov A. SIZ1/SIZ2 control of chromosome transmission fidelity is mediated by the sumoylation of topoisomerase II. Genetics. 2006;172:783-94 pubmed
    ..We propose a model for the positive control of the centromeric pool of Top2p, required for high segregation fidelity, by Smt3p modification. ..
  45. Kulikowicz T, Shapiro T. Distinct genes encode type II Topoisomerases for the nucleus and mitochondrion in the protozoan parasite Trypanosoma brucei. J Biol Chem. 2006;281:3048-56 pubmed
  46. Barker C, Hamlett J, Pennington S, Burrows F, Lundgren K, Lough R, et al. The topoisomerase II-Hsp90 complex: a new chemotherapeutic target?. Int J Cancer. 2006;118:2685-93 pubmed
  47. Zhang Y, Rowley J. Chromatin structural elements and chromosomal translocations in leukemia. DNA Repair (Amst). 2006;5:1282-97 pubmed
  48. Emmons M, Boulware D, Sullivan D, Hazlehurst L. Topoisomerase II beta levels are a determinant of melphalan-induced DNA crosslinks and sensitivity to cell death. Biochem Pharmacol. 2006;72:11-8 pubmed
    ..Finally, these results suggest non-redundant roles for these two isoforms in mediating repair of DNA crosslinks. ..
  49. Lemaitre J, Danis E, Pasero P, Vassetzky Y, Mechali M. Mitotic remodeling of the replicon and chromosome structure. Cell. 2005;123:787-801 pubmed
    ..These results indicate that mitotic conditioning is crucial to reset the chromatin structure of differentiated adult donor cells for embryonic DNA replication and suggest that it is an important step in nuclear cloning. ..
  50. Leontiou C, Lakey J, Lightowlers R, Turnbull R, Austin C. Mutation P732L in human DNA topoisomerase IIbeta abolishes DNA cleavage in the presence of calcium and confers drug resistance. Mol Pharmacol. 2006;69:130-9 pubmed
    ..This provides evidence for metal ion requirement for the phosphoryltransfer reaction of topoisomerase II and a possible mechanism for drug resistance. ..
  51. Salceda J, Fernandez X, Roca J. Topoisomerase II, not topoisomerase I, is the proficient relaxase of nucleosomal DNA. EMBO J. 2006;25:2575-83 pubmed
    ..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. ..
  52. McClendon A, Rodriguez A, Osheroff N. Human topoisomerase IIalpha rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. J Biol Chem. 2005;280:39337-45 pubmed
    ..These properties suggest that human topoisomerase IIalpha has the potential to alleviate torsional stress ahead of replication forks in an efficient and safe manner. ..
  53. Habermeyer M, Fritz J, Barthelmes H, Christensen M, Larsen M, Boege F, et al. Anthocyanidins modulate the activity of human DNA topoisomerases I and II and affect cellular DNA integrity. Chem Res Toxicol. 2005;18:1395-404 pubmed
    ..These data indicate substantial affinity to double-stranded DNA, which might contribute at least to the DNA strand breaking effect of anthocyanidins at higher concentrations (> or = 50 microM). ..
  54. Ju B, Lunyak V, Perissi V, Garcia Bassets I, Rose D, Glass C, et al. A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science. 2006;312:1798-802 pubmed
    ..Our data mechanistically link DNA topoisomerase IIbeta-dependent dsDNA breaks and the components of the DNA damage and repair machinery in regulated gene transcription. ..
  55. Pommier Y, Marchand C. Interfacial inhibitors of protein-nucleic acid interactions. Curr Med Chem Anticancer Agents. 2005;5:421-9 pubmed
    ..We discuss the implications of the interfacial inhibitor concept for drug discovery. ..
  56. Xiao H, Goodrich D. The retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes. Oncogene. 2005;24:8105-13 pubmed
    ..The functional status of pRb, therefore, may influence sensitivity to etoposide by facilitating the repair of trapped TOP2-DNA complexes as well as by enforcing cell cycle checkpoints. ..
  57. Uemura T, Tanagida M. Mitotic spindle pulls but fails to separate chromosomes in type II DNA topoisomerase mutants: uncoordinated mitosis. EMBO J. 1986;5:1003-10 pubmed
  58. Kaufmann W. Dangerous entanglements. Trends Mol Med. 2006;12:235-7 pubmed
    ..Ex vivo expansion of stem cells might have the unintended consequence of encouraging malignant progression. ..
  59. Haince J, Rouleau M, Poirier G. Transcription. Gene expression needs a break to unwind before carrying on. Science. 2006;312:1752-3 pubmed
  60. Lis J, Kraus W. Promoter cleavage: a topoIIbeta and PARP-1 collaboration. Cell. 2006;125:1225-7 pubmed
  61. Martincic D, Hande K. Topoisomerase II inhibitors. Cancer Chemother Biol Response Modif. 2005;22:101-21 pubmed
  62. Felix C, Kolaris C, Osheroff N. Topoisomerase II and the etiology of chromosomal translocations. DNA Repair (Amst). 2006;5:1093-108 pubmed
    ..This review will summarize the evidence for topoisomerase II involvement in the genesis of translocations and extension of the model to acute leukemia in infants characterized by similar MLL translocations. ..
  63. Germe T, Hyrien O. Topoisomerase II-DNA complexes trapped by ICRF-193 perturb chromatin structure. EMBO Rep. 2005;6:729-35 pubmed
    ..Chromatin perturbation by topo II clamps may explain some dominant cellular effects of ICRF-193. Nucleosome-driven bending of precatenane nodes may facilitate their unlinking by topo II during unperturbed replication...
  64. Kelly J, McRobert L, Baker D. Evidence on the chromosomal location of centromeric DNA in Plasmodium falciparum from etoposide-mediated topoisomerase-II cleavage. Proc Natl Acad Sci U S A. 2006;103:6706-11 pubmed
    ..These unusual properties suggest that P. falciparum chromosomes contain a class of "regional" centromere distinct from those described in other eukaryotes, including the human host. ..