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  • 1 Maltepe University, Istanbul, Turkey
  • | 2 Maltepe University, Istanbul, Turkey
  • | 3 Maltepe University, Istanbul, Turkey
  • | 4 Yeditepe University, Istanbul, Turkey
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Oxidative stress and chromosome missegregation are important factors that are linked to aneuploidy. A major reason for chromosome missegragation is the inappropriate activity of the spindle assembly checkpoint (SAC), a conserved surveillance mechanism that monitors the state of kinetochore-microtubule attachments to ensure equal chromosome segregation in mitosis. SAC-activation induces a prolonged mitotic arrest. Mitosis is considered the most vulnerable cell cycle phase to several external signals, therefore increasing the time cells spent in this phase via mitotic arrest induction by SAC-activating agents is favorable for cancer therapy. Cancer cells also display elevated oxidative stress due to abnormally high production of reactive oxygen species (ROS). However, the effect of increased oxidative stress on the duration of mitotic arrest remains largely unknown. In this study, we investigated the effect of H2O2-induced oxidative stress on the mitotic arrest induced by a SAC-activating agent (nocodazole) in Saccharomyces cerevisiae. Our data suggest that oxidative stress prolongs SAC-activation induced mitotic arrest in a dose dependent manner. We, in addition, investigated the effect of H2O2 treatment on the mitotic arrest induced independently of SAC-activation by using a conditional mutant (cdc23) and showed that the effect of H2O2-induced oxidative stress on mitotic arrest is independent of the SAC activity.

  • 1.

    Ando, K., Kakeji, Y., Kitao, H., Iimori, M., Zhao, Y., Yoshida, R., Oki, E., Yoshinaga, K., Matumoto, T., Morita, M., Sakaguchi, Y., Maehara, Y. (2010) High expression of BUBR1 is one of the factors for inducing DNA aneuploidy and progression in gastric cancer. Cancer Sci. 101, 639645.

    • Search Google Scholar
    • Export Citation
  • 2.

    Chan, K. S., Koh, C. G., Li, H. Y. (2012) Mitosis-targeted anti-cancer therapies: where they stand. Cell Death Dis. 3, e411-.

  • 3.

    D’Angiolella, V., Santarpia, C., Grieco, D. (2007) Oxidative stress overrides the spindle checkpoint. Cell Cycle 6, 576579.

  • 4.

    Draviam, V. M., Xie, S., Sorger, P. K. (2004) Chromosome segregation and genomic stability. Curr. Opin. Genet. Dev. 14, 120125.

  • 5.

    Duxin, J. P., Walter, J. C. (2015) What is the DNA repair defect underlying Fanconi anemia? Curr. Opin. Cell Biol. 37, 4960.

  • 6.

    Estrada, J. C., Torres, Y., Benguría, A., Dopazo, A., Roche, E., Carrera-Quintanar, L., Pérez, R. A., Enríquez, J. A., Torres, R., Ramírez, J. C., Samper, E., Bernad, A. (2013) Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy. Cell Death Dis. 4, e691-

    • Search Google Scholar
    • Export Citation
  • 7.

    Flattery-O’Brien, J. A., Dawes, I. W. (1998) Hydrogen peroxide causes RAD9-dependent cell cycle arrest in G2 in Saccharomyces cerevisiae whereas menadione causes G1 arrest independent of RAD9 function. J. Biol. Chem. 273, 85648571.

    • Search Google Scholar
    • Export Citation
  • 8.

    Gorla, G. R., Malhi, H., Gupta, S. (2001) Polyploidy associated with oxidative injury attenuates proliferative potential of cells. J. Cell Sci. 114, 29432951.

    • Search Google Scholar
    • Export Citation
  • 9.

    Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D., Paull, T. T. (2010) ATM activation by oxidative stress. Science 330, 517521.

  • 10.

    Hoyt, M. A., Stearns, T., Botstein, D. (1990) Chromosome instability mutants of Saccharomyces cerevisiae that are defective in microtubule-mediated processes. Mol. Cell. Biol. 10, 223234.

    • Search Google Scholar
    • Export Citation
  • 11.

    Hughes, A. F. (1950) The effect of inhibitory substances on cell division; a study on living cells in tissue cultures. Q. J. Microsc. Sci. 91, 251277.

    • Search Google Scholar
    • Export Citation
  • 12.

    Irniger, S., Piatti, S., Michaelis, C., Nasmyth, K. (1995) Genes involved in sister chromatid separation are needed for B-type cyclin proteolysis in budding yeast. Cel1 81, 269278.

    • Search Google Scholar
    • Export Citation
  • 13.

    Kim, S. Y., Jo, H. Y., Kim, M. H., Cha, Y. Y., Choi, S. W., Shim, J. H., Kim, T. J., Lee, K. Y. (2008) H2O2-dependent hyperoxidation of peroxiredoxin 6 (Prdx6) plays a role in cellular toxicity via up-regulation of iPLA2 activity. J. Biol. Chem. 283, 3356333568.

    • Search Google Scholar
    • Export Citation
  • 14.

    Kops, G. J., Weaver, B. A., Cleveland, D. W. (2005) On the road to cancer: aneuploidy and the mitotic checkpoint. Nat. Rev. Cancer 5, 773785.

    • Search Google Scholar
    • Export Citation
  • 15.

    Kraniak, J. M., Abrams, J., Nowak, J. E., Tainsky, M. A. (2006) Antioxidant agents transiently inhibit aneuploidy progression in Li-Fraumeni cell strains. Mol. Carcinog. 45, 141156.

    • Search Google Scholar
    • Export Citation
  • 16.

    Kushnirov, V. V. (2000) Rapid and reliable protein extraction from yeast. Yeast (Chichester, England). 16, 857860.

  • 17.

    Lau, D. T., Murray, A. W. (2012) Mad2 and Mad3 cooperate to arrest budding yeast in mitosis. Curr. Biol. 22, 180190.

  • 18.

    Lawrence, K. S., Engebrecht, J. (2015) The spindle assembly checkpoint: More than just keeping track of the spindle. Trends. Cell. Mol. Biol. 10, 141150.

    • Search Google Scholar
    • Export Citation
  • 19.

    Liou, G. Y., Storz, P. (2010) Reactive oxygen species in cancer. Free Radic. Res. 44, 10.3109/10715761003667554.

  • 20.

    Madeo, F., Fröhlich, E., Ligr, M., Grey, M., Sigrist, S. J., Wolf, D. H., Fröhlich, K. U. (1999) Oxygen stress: a regulator of apoptosis in yeast. J. Cell Biol. 145, 757767.

    • Search Google Scholar
    • Export Citation
  • 21.

    Magenta, A., Fasanaro, P., Romani, S., Di Stefano, V., Capogrossi, M. C., Martelli, F. (2008) Protein phosphatase 2A subunit PR70 interacts with pRb and mediates its dephosphorylation. Mol. Cell. Biol. 28, 873882.

    • Search Google Scholar
    • Export Citation
  • 22.

    Michel, L. S., Liberal, V., Chatterjee, A., Kirchwegger, R., Pasche, B., Gerald, W., Dobles, M., Sorger, P. K., Murty, V. V., Benezra, R. (2001) MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409, 355359.

    • Search Google Scholar
    • Export Citation
  • 23.

    Mukhtar, E., Adhami, V. M., Mukhtar, H. (2014) Targeting Microtubules by Natural Agents for Cancer Therapy. Mol. Cancer Ther. 13, 275284.

    • Search Google Scholar
    • Export Citation
  • 24.

    Musacchio, A. (2015) The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics. Curr. Biol. 25, R10021018.

  • 25.

    Pelicano, H., Carney, D., Huang, P. (2004) ROS stress in cancer cells and therapeutic implications. Drug Resist. Updat. 7, 97110.

  • 26.

    Pérez de Castro, I., de Cárcer, G., Malumbres, M. (2007) A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis 28, 899912.

    • Search Google Scholar
    • Export Citation
  • 27.

    Roh, M., Abdulkadir, R., van der Meer, S. A. (2012) Tumorigenic polyploid cells contain elevated ROS and ARE selectively targeted by antioxidant treatment. J. Cell. Physiol. 227, 801812.

    • Search Google Scholar
    • Export Citation
  • 28.

    Schieber, M., Chandel, N. S. (2014) ROS Function in Redox Signaling and Oxidative Stress. Curr. Biol. 24, R453R462.

  • 29.

    Shapira, M., Segal, E., Botstein, D. (2004) Disruption of yeast forkhead-associated cell cycle transcription by oxidative stress. Mol. Biol. Cell 15, 56595669.

    • Search Google Scholar
    • Export Citation
  • 30.

    Stobbe, C. C., Park, S. J., Chapman, J. D. (2002) The radiation hypersensitivity of cells at mitosis. Int. J. Radiat. Biol. 78, 11491157.

    • Search Google Scholar
    • Export Citation
  • 31.

    Stukenberg, P. T., Burke, D. J. (2015) Connecting the microtubule attachment status of each kinetochore to cell cycle arrest through the spindle assembly checkpoint. Chromosoma 124, 463480.

    • Search Google Scholar
    • Export Citation
  • 32.

    Tominaga, H., Kodama, S., Matsuda, N., Suzuki, K., Watanabe, M. (2004) Involvement of reactive oxygen species (ROS) in the induction of genetic instability by radiation. J. Radiat. Res. 45, 181188.

    • Search Google Scholar
    • Export Citation
  • 33.

    van de Wetering, C. I., Coleman, M. C., Spitz, D. R., Smith, B. J., Knudson, C. M. (2008) Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma. Free Radic. Biol. Med. 44, 16771686.

    • Search Google Scholar
    • Export Citation
  • 34.

    Varbiro, G., Veres, B., Gallyas, F. Jr., Sumegi, B. (2001) Direct effect of Taxol on free radical formation and mitochondrial permeability transition. Free Radic. Biol. Med. 31, 548558.

    • Search Google Scholar
    • Export Citation
  • 35.

    Wang, C. Y., Liu, L. N., Zhao, Z. B. (2013) The role of ROS toxicity in spontaneous aneuploidy in cultured cells. Tissue Cell 45, 4753.

    • Search Google Scholar
    • Export Citation
  • 36.

    Wang, G. F., Dong, Q., Bai, Y., Yuan, J., Xu, Q., Cao, C., Liu, X. (2017) Oxidative stress induces mitotic arrest by inhibiting Aurora A-involved mitotic spindle formation. Free Radic. Biol. Med. 103, 177187.

    • Search Google Scholar
    • Export Citation
  • 37.

    Wang, Q., Liu, T., Fang, Y., Xie, S., Huang, X., Mahmood, R., Ramaswamy, G., Sakamoto, K. M., Darzynkiewicz, Z., Xu, M., Dai, W. (2004) BUBR1 deficiency results in abnormal megakaryopoiesis. Blood. 103, 12781285.

    • Search Google Scholar
    • Export Citation
  • 38.

    Weaver, B. A., Cleveland, D. W. (2006) Does aneuploidy cause cancer? Curr. Opin. Cell Biol. 18, 658667.