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Somatic Cell and Molecular Genetics

, Volume 25, Issue 1, pp 9–26 | Cite as

A Combination of Genetic Suppressor Elements Produces Resistance to Drugs Inhibiting DNA Replication

  • Victor V. Levenson ChernokhvostovEmail author
  • Ekkehart Lausch
  • Deborah J. Kirschling
  • Eugenia V. Broude
  • Irina A. Davidovich
  • Scot Libants
  • Vera Fedosova
  • Igor B. Roninson
Article

Abstract

Many anticancer drugs inhibit DNA replication. To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. These results indicate that combined effects of GSEs derived from these four genes increase cellular resistance to replication-inhibiting drugs, possibly by inhibiting drug-induced senescence.

Keywords

Doxorubicin Hydroxyurea Fibrosarcoma Zinc Finger Protein Fibrosarcoma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Victor V. Levenson Chernokhvostov
    • 1
    Email author
  • Ekkehart Lausch
    • 1
  • Deborah J. Kirschling
    • 1
  • Eugenia V. Broude
    • 1
  • Irina A. Davidovich
    • 1
  • Scot Libants
    • 1
  • Vera Fedosova
    • 1
  • Igor B. Roninson
    • 1
  1. 1.Department of Molecular GeneticsUniversity of Illinois at ChicagoChicago

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