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Gene Review

TOP1  -  DNA topoisomerase 1

Saccharomyces cerevisiae S288c

Synonyms: DNA topoisomerase I, MAK1, MAK17, Maintenance of killer protein 1, YOL006C
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Disease relevance of TOP1


High impact information on TOP1

  • Expression of a plasmid-borne TOP1 or TOP2 gene in the strain leads to the integation of the extrachromosomal rDNA rings back into the chromosomal rDNA cluster [6].
  • In a yeast DNA topoisomerase double mutant TG205 (delta top1 top2-4), over half of the rDNA is present as extrachromosomal rings containing one 9 kb unit of the rDNA gene or tandem repeats of it [6].
  • Measurements at various temperatures of the linking number of yeast 2 microns plasmid DNA in wild-type cells and in cells bearing mutations in the DNA topoisomerase I and II genes show that bulk 2 microns plasmid minichromosome are maintained in a relaxed state by the combined action of topoisomerases I and II [7].
  • Need for DNA topoisomerase activity as a swivel for DNA replication for transcription of ribosomal RNA [8].
  • These data indicate that TOP1 (encoding topo I) and TRF4 participate in overlapping or dependent steps in mitotic chromosome condensation and serve to define a previously unrecognized biological function of topo I [9].

Chemical compound and disease context of TOP1


Biological context of TOP1

  • The high frequency of mitotic recombination within the rDNA cluster in topoisomerase mutants shows that both TOP1 and TOP2 are required for suppression of recombination in this region of the genome [12].
  • The defect in the top1 trf4-ts mutant is sensed by the MAD1-dependent spindle assembly checkpoint but not by the RAD9-dependent DNA damage checkpoint, further supporting the notion that chromosome structure influences spindle assembly [9].
  • DNA topoisomerase I (topo I) is known to participate in the process of DNA replication, but is not essential in Saccharomyces cerevisiae [9].
  • Direct examination of rDNA-containing mitotic chromosomes demonstrates that a top1 trf4-ts mutant fails both to establish and to maintain chromosome condensation in the rDNA at mitosis [9].
  • Our results show that Tdp1 plays more general roles in DNA repair than repair of Top1 mediated DNA damage, and may participate in repairing many types of base damage to DNA [13].

Anatomical context of TOP1

  • Moreover, in the mammalian cell culture system, hydrogen peroxide-induced growth inhibition and apoptosis were shown to be partly TOP1-dependent as evidenced by a specific increase in resistance to hydrogen peroxide in TOP1-deficient P388/CPT45 murine leukemia cells as compared with their TOP1-proficient parental cell line P388 [2].
  • A mitochondrial type I-like, ATP-independent, DNA topoisomerase, isolated from highly purified yeast mitochondria, is genetically related to nuclear topoisomerase I. We found that the mitochondrial topoisomerase activity cannot be detected in yeast mitochondrial extracts prepared from strains in which the topoisomerase I gene (TOP1) is disrupted [14].
  • Purification and functional characterization of type II DNA topoisomerase from rat testis and comparison with topoisomerase II from liver [15].
  • COS cells transfected with an SV40-based vector were treated with camptothecin (CPT), a eukaryotic DNA topoisomerase I (TOP1) poison which induces TOP1-mediated DNA damage [16].

Associations of TOP1 with chemical compounds

  • The ethyl methanesulfonate-induced hpr1-1 mutation is a single-base change that produces a stop codon at amino acid 559 coding for a protein that lacks the carboxy-terminal TOP1 homologous region [17].
  • Deletion of the Ulp2 SUMO protease failed to restore ubc9-10 cell resistance to Top1p poisons or hydroxyurea yet adversely affected wild-type TOP1 cell genetic stability and sensitivity to hydroxyurea [18].
  • Accidental or drug-induced interruption of the breakage and reunion cycle of eukaryotic topoisomerase I (Top1) yields complexes in which the active site tyrosine of the enzyme is covalently linked to the 3' end of broken DNA [19].
  • Evidence has been obtained that such an in vivo increase in linking number depends on (i) the activity of DNA topoisomerase I and of no other enzyme and (ii) ethanol addition, not on the release from glucose repression [20].
  • Assays of DNA topoisomerase I in lysates of camptothecin-resistant transformants identified one with nearly the same level of the enzyme as transformants of unmutagenized YCpGAL1-hTOP1, and a single mutation changing Gly363 to a cysteine was found in this mutant [21].

Physical interactions of TOP1

  • None of these genes is required for viability and all SLX null mutations are synthetically lethal with mutations in TOP3, encoding the SGS1-interacting DNA topoisomerase [22].

Regulatory relationships of TOP1

  • The fact that top1 suppressed the growth defect of gcr3 suggested an interaction between those two genes also [23].
  • SCT1 mutants suppress the camptothecin sensitivity of yeast cells expressing wild-type DNA topoisomerase I [11].

Other interactions of TOP1

  • Strains with a null mutation in the TOP1 gene (encoding topoisomerase I) or a ts mutation in the TOP2 gene (encoding topoisomerase II) grown at a semipermissive temperature show 50- to 200-fold higher frequencies of mitotic recombination in rDNA relative to TOP+ controls [12].
  • Thus, tdp1 rad1 cells (including the catalytic point mutant rad1-D869A) not only are highly sensitive to the Top1 poison camptothecin but also exhibit a TOP1-dependent growth delay [24].
  • HPR1, a novel yeast gene that prevents intrachromosomal excision recombination, shows carboxy-terminal homology to the Saccharomyces cerevisiae TOP1 gene [17].
  • Yeast SCT1 mutants were isolated in a screen for mutations in genes other than TOP1 that result in camptothecin resistance [25].
  • The two-hybrid system was used to identify yeast genes encoding proteins that interact with DNA topoisomerase I. Two new genes were found and named TOF1 and TOF2 [26].

Analytical, diagnostic and therapeutic context of TOP1


  1. Cloning of yeast TOP1, the gene encoding DNA topoisomerase I, and construction of mutants defective in both DNA topoisomerase I and DNA topoisomerase II. Goto, T., Wang, J.C. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  2. Hydrogen peroxide induces topoisomerase I-mediated DNA damage and cell death. Daroui, P., Desai, S.D., Li, T.K., Liu, A.A., Liu, L.F. J. Biol. Chem. (2004) [Pubmed]
  3. Overexpression of type I topoisomerases sensitizes yeast cells to DNA damage. Nitiss, J.L., Nitiss, K.C., Rose, A., Waltman, J.L. J. Biol. Chem. (2001) [Pubmed]
  4. Identification of a vaccinia virus gene encoding a type I DNA topoisomerase. Shuman, S., Moss, B. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  5. Platinated DNA adducts enhance poisoning of DNA topoisomerase I by camptothecin. van Waardenburg, R.C., de Jong, L.A., van Eijndhoven, M.A., Verseyden, C., Pluim, D., Jansen, L.E., Bjornsti, M.A., Schellens, J.H. J. Biol. Chem. (2004) [Pubmed]
  6. A subthreshold level of DNA topoisomerases leads to the excision of yeast rDNA as extrachromosomal rings. Kim, R.A., Wang, J.C. Cell (1989) [Pubmed]
  7. Both DNA topoisomerases I and II relax 2 micron plasmid DNA in living yeast cells. Saavedra, R.A., Huberman, J.A. Cell (1986) [Pubmed]
  8. Need for DNA topoisomerase activity as a swivel for DNA replication for transcription of ribosomal RNA. Brill, S.J., DiNardo, S., Voelkel-Meiman, K., Sternglanz, R. Nature (1987) [Pubmed]
  9. Mitotic chromosome condensation in the rDNA requires TRF4 and DNA topoisomerase I in Saccharomyces cerevisiae. Castaño, I.B., Brzoska, P.M., Sadoff, B.U., Chen, H., Christman, M.F. Genes Dev. (1996) [Pubmed]
  10. Peptide sequencing and site-directed mutagenesis identify tyrosine-727 as the active site tyrosine of Saccharomyces cerevisiae DNA topoisomerase I. Lynn, R.M., Bjornsti, M.A., Caron, P.R., Wang, J.C. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  11. SCT1 mutants suppress the camptothecin sensitivity of yeast cells expressing wild-type DNA topoisomerase I. Kauh, E.A., Bjornsti, M.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  12. Mitotic recombination in the rDNA of S. cerevisiae is suppressed by the combined action of DNA topoisomerases I and II. Christman, M.F., Dietrich, F.S., Fink, G.R. Cell (1988) [Pubmed]
  13. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Nitiss, K.C., Malik, M., He, X., White, S.W., Nitiss, J.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  14. On the relationship of the ATP-independent, mitochondrial associated DNA topoisomerase of Saccharomyces cerevisiae to the nuclear topoisomerase I. Wang, J., Kearney, K., Derby, M., Wernette, C.M. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  15. Purification and functional characterization of type II DNA topoisomerase from rat testis and comparison with topoisomerase II from liver. Galande, S., Muniyappa, K. Biochim. Biophys. Acta (1996) [Pubmed]
  16. Plasmid linking number change induced by topoisomerase I-mediated DNA damage. Duann, P., Sun, M., Lin, C.T., Zhang, H., Liu, L.F. Nucleic Acids Res. (1999) [Pubmed]
  17. HPR1, a novel yeast gene that prevents intrachromosomal excision recombination, shows carboxy-terminal homology to the Saccharomyces cerevisiae TOP1 gene. Aguilera, A., Klein, H.L. Mol. Cell. Biol. (1990) [Pubmed]
  18. Defects in SUMO (small ubiquitin-related modifier) conjugation and deconjugation alter cell sensitivity to DNA topoisomerase I-induced DNA damage. Jacquiau, H.R., van Waardenburg, R.C., Reid, R.J., Woo, M.H., Guo, H., Johnson, E.S., Bjornsti, M.A. J. Biol. Chem. (2005) [Pubmed]
  19. Repair of topoisomerase I covalent complexes in the absence of the tyrosyl-DNA phosphodiesterase Tdp1. Liu, C., Pouliot, J.J., Nash, H.A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  20. DNA topoisomerase I controls the kinetics of promoter activation and DNA topology in Saccharomyces cerevisiae. Di Mauro, E., Camilloni, G., Verdone, L., Caserta, M. Mol. Cell. Biol. (1993) [Pubmed]
  21. Camptothecin resistance from a single mutation changing glycine 363 of human DNA topoisomerase I to cysteine. Benedetti, P., Fiorani, P., Capuani, L., Wang, J.C. Cancer Res. (1993) [Pubmed]
  22. Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae. Mullen, J.R., Kaliraman, V., Ibrahim, S.S., Brill, S.J. Genetics (2001) [Pubmed]
  23. Mutations in GCR3, a gene involved in the expression of glycolytic genes in Saccharomyces cerevisiae, suppress the temperature-sensitive growth of hpr1 mutants. Uemura, H., Pandit, S., Jigami, Y., Sternglanz, R. Genetics (1996) [Pubmed]
  24. Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage. Vance, J.R., Wilson, T.E. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  25. Camptothecin sensitivity is mediated by the pleiotropic drug resistance network in yeast. Reid, R.J., Kauh, E.A., Bjornsti, M.A. J. Biol. Chem. (1997) [Pubmed]
  26. Identification and characterization of the genes for two topoisomerase I-interacting proteins from Saccharomyces cerevisiae. Park, H., Sternglanz, R. Yeast (1999) [Pubmed]
  27. The topoisomerase I gene from Candida albicans. Jiang, W., Gerhold, D., Kmiec, E.B., Hauser, M., Becker, J.M., Koltin, Y. Microbiology (Reading, Engl.) (1997) [Pubmed]
  28. The genetic control of DS-RNA virus-like particles associated with Saccharomyces cerevisiae killer yeast. Mitchell, D.J., Herring, A.J., Bevan, E.A. Heredity (1976) [Pubmed]
  29. A novel active DNA topoisomerase I in Leishmania donovani. Villa, H., Otero Marcos, A.R., Reguera, R.M., Balaña-Fouce, R., García-Estrada, C., Pérez-Pertejo, Y., Tekwani, B.L., Myler, P.J., Stuart, K.D., Bjornsti, M.A., Ordóñez, D. J. Biol. Chem. (2003) [Pubmed]
  30. Functional dissection of the C-terminal domain of type II DNA topoisomerase from the kinetoplastid hemoflagellate Leishmania donovani. Sengupta, T., Mukherjee, M., Mandal, C., Das, A., Majumder, H.K. Nucleic Acids Res. (2003) [Pubmed]
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